Advances in nano-drug delivery systems for metallic compounds in cancer therapy: challenges and future perspectives

Abstract

Metallic compounds have shown great promise as anticancer treatments because of their varied mechanisms of action, decreased side effects, and ability to overcome drug resistance. The search for alternative metal-based therapies has been driven by the severe toxicity, drug resistance, and poor selectivity of platinum-based complexes like cisplatin, carboplatin, and oxaliplatin, despite their notable clinical effectiveness. Their clinical translation is made difficult by issues such as off-target toxicity, low absorption, and poor solubility. These findings highlight the potential of nanomedicine to enhance therapeutic efficacy and patient compliance. Similarly, a range of nanocarriers have been investigated for the precise and targeted administration of metallic medications, including polymeric NPs, inorganic materials, and lipid-based, peptide-based, and carbon-based systems. These nanocarriers offer several advantages such as enhanced solubility, stability, cellular uptake and biocompatibility while reducing systemic toxicity and ensuring controlled and precise drug release of the metal complexes. This review article emphasizes on the impact of nanomaterials on the delivery of metallic anticancer drugs across various types of cancer. It discusses the key nanocarriers employed for targeted delivery of metal complexes, their effects on malignant cells, existing challenges, and future opportunities for optimizing metallic cancer therapies. Finally, we propose strategies to enhance the efficacy and safety of these nano-based metallic therapies.

---

Subin Joseph

Subin Joseph earned his Master's in Nanoscience from the Central University of Gujarat, India. His Master's thesis focused on the synthesis of novel nano drug delivery carriers for cancer therapy. Currently, he is pursuing Ph. D. at Vellore Institute of Technology, Vellore, under the supervision of Dr. Priyankar Paira, focusing on the synthesis of organometallic compounds and their advanced nano drug delivery systems for anticancer therapy applications.

Dr. Rinku Chakrabarty

Dr. Rinku Chakrabarty embarked on her academic journey at IIEST, Shibpur, India for her Ph.D. under the guidance of Prof. Shyamaprosad Goswami in 2011, focusing on Supramolecular Chemistry, followed by postdoctoral studies at the University of Witwatersrand, Johannesburg, South Africa, where she was involved in the synthesis of rare-earth-based molecular systems as MRI agents. Her passion for academia led her to assume the role of an Assistant Professor in the Department of Chemistry at Alipurduar University. Her research pursuits are centered on nanomaterials, molecular sensing and bioinorganic chemistry, showcasing her unwavering commitment to the advancement of the field of Chemistry.

Dr. Priyankar Paira

Dr. Priyankar Paira, MRSC, Associate Professor, VIT, Vellore, Tamilnadu, India, received his Ph.D. from the Indian Institute of Chemical Biology (IICB), Jadavpur University, Kolkata and his Post Doctorate degree from National University of Singapore. He is a Bioinorganic and Medicinal Chemist with 12 years of experience. He has over 100 publications in reputed international journals having citations (2789) and h-Index (29). He also has 3 patents in Medicinal Chemistry. He has successfully completed three DST projects, two ICMR projects and currently working on one CSIR project. He is associated with professional bodies like ACS, RSC and SBIC.

---

Introduction

Cancer is a complex and potentially fatal condition marked by the uncontrolled growth and dissemination of cancerous cells. Cell growth and death are regulated by normal mechanisms that are disrupted by genetic mutations, resulting in the formation of tumors. Globally, cancer accounts for one in every six deaths caused by disease, making it a major public health concern.¹ The development of cancer is a result of multiple key factors, that include a person's genetic makeup, and exposure to several environmental hazards such as chemical carcinogens, for instance, tobacco smoke, asbestos, and aflatoxins; physical agents like UV and ionizing radiation; and biological influences.

Approaches for treating cancer are tailored to the type and progression of the disease and encompass conventional methods such as surgery, chemotherapy, and radiation therapy, as well as more innovative treatments including immunotherapy, gene therapy, hormone therapy, sonodynamic therapy, photodynamic therapy (PDT), and combination therapies.^2,3 In this context, metal-based anticancer compounds, or metallodrugs, have been instrumental in contemporary cancer treatment protocols.

The serendipitous discovery of cisplatin in 1965⁴ represented a major turning point in cancer treatment and led to substantial progress in the field of bioinorganic chemistry. Platinum-based medications that are clinically approved, such as cisplatin, carboplatin, and oxaliplatin, have demonstrated significant effectiveness against several types of cancer, including testicular, ovarian, and lung cancers.^5–7 Their employment is frequently restricted by significant adverse effects, resistance, and off-target toxicity, leading to a search for the next-generation metal-based compounds that possess improved selectivity and decreased toxicity.

Metal complexes demonstrate a variety of mechanisms through which they exert anticancer effects.⁸ Platinum-based drugs form covalent bonds with DNA, which interfere with both replication and transcription processes, resulting in cell death. Gold and platinum derivatives have shown antiangiogenic properties by disrupting vascular endothelial growth factor (VEGF) signaling pathways, which in turn prevents the formation of new blood vessels that feed tumors.⁹

Ruthenium complexes have garnered considerable attention owing to their promising abilities in combating cancer and preventing metastasis. Unlike platinum compounds, ruthenium can be found in several oxidation states (II, III, and IV), which enables it to become selectively activated within the reducing tumor environment.¹⁰ This redox-sensitive behavior reduces damage to healthy cells and enhances the accuracy of targeted treatments. Ruthenium's ability to mimic iron also enables it to bind plasma proteins like transferrin, thereby facilitating preferential tumor accumulation. Ruthenium complexes such as NAMI-A, KP1019, KP1339, and TLD1433, which have been clinically studied, have been impacted by issues including low solubility and negative side effects, resulting in the discontinuation of some of these candidates.^11,12 KP1339 continues to be tested in late-stage clinical trials, while TLD1433 is currently undergoing Phase II trials for PDT in bladder cancer treatment. Half-sandwich Ru(II)–arene complexes are notably attractive options because of their structural adaptability, lipophilicity, and the ability to easily penetrate cells.¹³

Gold(I) compounds function through mechanisms different from those of DNA-targeting platinum drugs. These compounds show a strong preference for sulfur-containing biomolecules, which makes enzymes such as thioredoxin reductase, glutathione reductase, and cysteine proteases their main intracellular targets.^14–16 Gold(I) complexes have shown potential to inhibit the growth, migration, and blood vessel formation of cancer cells, and may also cause the cells to die and trigger an immune response.¹⁷

In addition to platinum, ruthenium, and gold, several other metal-based complexes are being investigated for their ability to fight cancer. Research has demonstrated that osmium and rhodium complexes possess the capability to cause oxidative stress, while cobalt and copper complexes interfere with crucial cellular functions, thus initiating apoptosis. Rhenium compounds are attracting interest in photodynamic therapy because their photophysical characteristics offer several advantages, similar to those of ruthenium-based analogues. Arsenic trioxide and copper complexes amongst other metals induce cytotoxic effects through the production of reactive oxygen species, that results in oxidative stress, damage to mitochondria, and apoptosis.^18,19

Despite recent progress, the use of metallodrugs in a clinical setting continues to be hindered by difficulties, including low aqueous solubility, systemic toxicity, and the problem of multidrug resistance. Many researchers are exploring the synthesis of various types of metal complexes and their application in cancer therapy by resolving these issues.^20–26 In this context, nanotechnology offers a highly transformative solution.²⁷ Metal complex nanoformulations, including lipid-based nanoparticles, and various material-based delivery systems, increase solubility of the drug and optimise drug absorption and distribution in the body, allowing targeted delivery to tumors via the enhanced permeability and retention (EPR) effect, and facilitating controlled and various stimuli-responsive release of the drug.

This review focuses on the advancements in nano-based metal complexes for cancer treatment particularly those developed in the last four years, highlighting their advantages over conventional methods, and potential future improvements in addressing the challenges associated with metal-based cancer therapy.

Advances in nano-drug delivery systems for metallic compounds

A range of nanocarriers have been investigated for the precise and targeted administration of metal complexes, including lipid-based, polymer-based, inorganic, protein, peptide and carbon-based nanocarrier systems. These nanocarriers offer several advantages such as enhanced solubility, stability, and biocompatibility while reducing systemic toxicity. Additionally, the nanoparticles can enhance the concentration of the anticancer drug at tumor lesions via their enhanced permeability and retention (EPR) effect, thus therapeutic effect is increased. Furthermore, nanocarriers can enable stimuli-responsive delivery by interacting with the unique tumor microenvironment (TME) or responding to external stimuli like light, ultrasound, magnetic field, and temperature, and thereby ensuring controlled and precise drug release.

Lipid-based nanocarriers

In the last decade, lipid-based nanocarriers have developed into highly efficient delivery systems for pharmaceutical medications, particularly those with limited bioavailability. These carriers provide notable benefits, including outstanding biocompatibility, minimal toxicity, high drug loading capacity, and cost-efficient large-scale manufacturing.^28,29 The most well-known types include liposomes, nanostructured lipid carriers (NLCs), solid lipid nanoparticles (SLNs), and lipid–polymer hybrid nanoparticles. These formulations have garnered significant interest, particularly liposomes, which can effectively encapsulate hydrophilic, hydrophobic, and amphiphilic compounds. These formulations stabilise drugs, prevent unnecessary interactions, and enable precise and targeted delivery, especially through the EPR effect in tumors. Notably, liposomal formulations, such as Lipoplatin (liposomal cisplatin), display notably enhanced tumor accumulation and decreased systemic toxicity when compared to non-encapsulated drugs.^28,30 The enhanced liposomal structure is responsible for improved performance, which is a result of increased cellular uptake and prolonged intracellular release.

Several innovative studies have demonstrated the therapeutic potential of liposomal formulations carrying metal complexes.

Liposomes. Targeted drug delivery systems primarily utilize liposomes as the most extensively investigated nanocarriers. Spherical lipid vesicles, known as liposomes, typically range from 50 to 500 nm in diameter, and consist of one or more lipid layers formed by emulsifying natural or synthetic lipids in an aqueous solution.³¹ Due to their stability, biocompatibility, ease of synthesis, and exceptional drug loading efficiency,³² along with high bioavailability, as well as the use of safe excipients,^33,34 liposomes and nanoemulsions are recurrently used nanoparticles in nanomedicine. Due to their size and unique combinations of hydrophobic and hydrophilic properties, as well as their capacity to enclose drug molecules either within the aqueous interior of the vesicles or within the lipophilic membrane, liposomes are viewed as potentially effective drug delivery systems. Multiple liposomal-based drug delivery systems have received FDA approval for disease treatment in the market.^35,36 In addition, liposomes are well-suited for diagnostic and therapeutic purposes through various routes of administration, such as ocular,³⁷ oral,³⁸ pulmonary,³⁹ transdermal,⁴⁰ and parenteral.^41,42

The advancement of nanodrug delivery systems has opened up new pathways for overcoming chemotherapy resistance in cancer treatment, especially with metal-based complexes. Cisplatin remains a fundamental component of anticancer treatment; however, resistance to it greatly restricts its effectiveness in clinical settings. New approaches, including metal complex nanocarriers, have been investigated to address this issue. A recent study was conducted by Ming Jiang et al. on the In(III) 2-pyridinecarboxaldehyde thiosemicarbazone compound (1), which has shown significant anticancer properties against cisplatin-resistant MCF-7/DDP cells (Fig. 1). The agent containing indium(III) was encapsulated within liposomes prepared by the thin-layer evaporation technique. This not only led to a greater accumulation of the agent in tumor cells due to a pH-responsive release mechanism, but it also significantly improved the therapeutic outcomes in comparison with the free drug and cisplatin. The encapsulated form exhibited several multi-targeting actions, including inducing apoptosis and lethal autophagy in tumor cells, suppressing the drug-resistance pathways such as PI3K/AKT and P-gp expression, repolarizing M2 macrophages to an M1 phenotype within the immunosuppressive tumor environment, and inhibiting tumor angiogenesis. In addition, the 5 b-Lip formulation demonstrated a significant level of tumor suppression with minimal side effects throughout the body, highlighting the potential of nanotechnology-based delivery systems in metal complex treatment. This research showcases the benefits of combining chemotherapy with immunotherapy using intelligent nanocarrier systems, offering a strategic approach for developing the next generation of metal-based anticancer agents that can overcome drug resistance.⁴³

Fig. 1 Graphical representation of different nanocarriers used in metal complex-based cancer therapy and its outcome.

Researchers are now using lipid-based nanocarriers to deliver treatments beyond conventional chemotherapy, incorporating them into a new and rapidly developing approach for cancer therapy known as gas therapy. Nitric oxide (NO), hydrogen sulfide (H₂S), carbon monoxide (CO), and sulfur dioxide (SO₂) are gasotransmitters that are crucial in numerous physiological processes and have shown promise in treating inflammation, cancer, and cardiovascular diseases. A nanosystem created by Yaw Opoku-Damoah et al., containing manganese complex 2, includes a lipid coating and responds to low-intensity ultrasound waves of 1.25 W cm⁻² by releasing NO and CO simultaneously. A new cancer treatment approach is presented, involving a lipid-coated, ultrasound-sensitive nanosystem (LUGCF-1 : 1), which delivers carbon monoxide (CO) and nitric oxide (NO) to cancer cells at the same time. The lipid bilayer consists of hydrophobic CO-releasing molecules (CORMs) and electrostatically attached lanthanide-doped nanoparticles that are linked to the hydrophilic GSNO, a NO donor, which is also modified with folate ligands for targeted delivery. The nanoplatform initiates selective and efficient gas release when exposed to low-intensity ultrasound at a power density of 1.25 W cm⁻² for 5 minutes, as demonstrated by fluorescence imaging with probes sensitive to CO and NO. At lower intensities, NO release was rapid and complete, whereas CO exhibited a more gradual release profile, facilitating controlled dual-gas delivery. Furthermore, carbon monoxide enhanced the production of mitochondrial ROS, and nitrogen oxide reacted with ROS to form reactive nitrogen species, including peroxynitrite, thus amplifying oxidative stress and inducing apoptosis. The combination treatment displayed synergistic cytotoxic effects, with an IC₅₀ value of 2.28 μg mL⁻¹ and a combination index of more than 1.4, as well as roughly three times higher ROS levels than those of single-gas systems. In vivo, ultrasound treatment resulted in approximately 87% tumor suppression in mice with CT26 tumors, which is substantially higher than that of single-gas treatments, without causing systemic toxicity. This research establishes this system as a reliable, safe, and highly effective method for ultrasound-enhanced synergistic gas therapy, providing a promising approach for non-surgical, targeted cancer treatment.⁴⁴

In 2022, Sumithaa et al. synthesized new half-sandwich Ru(II)–p-cymene complexes that incorporated natural compounds derived from ginger, specifically, [Ru(η⁶-p-cymene)(6-gingerol)(Cl)] (3) (Fig. 2). Studies revealed that these complexes displayed significantly higher cytotoxicity than cisplatin, while also presenting a high level of toxicity to healthy fetal lung fibroblasts. The Ru complex (3) was encapsulated in a liposomal formulation based on polydiacetylene to reduce its toxicity and increase its therapeutic effectiveness. The formulation was prepared using thin-film hydration with 10,12-pentacosadiynoic acid (PCDA) and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC). The liposomal system led to a substantial 20-fold increase in cellular uptake and a rise in reactive oxygen species (ROS) production within cancer cells. Encapsulation effectively maintained the ability of the complex to prevent metastasis. The authors suggest additional optimisation through surface alterations with targeted ligands and release mechanisms that respond to specific stimuli, such as temperature or pH changes, to enhance therapeutic results.⁴⁵

Fig. 2 Schematic illustration of delivery of various liposome-encapsulated metal complexes to cancer cells.

Siva et al. synthesised two phenanthro[9,10-d]imidazole-based ligands and their Zn(II) complexes (4) displaying intrinsic fluorescence for imaging purposes (Fig. 2). The complexes were encapsulated in liposomes formed from DMPC resulting in an increase in cellular uptake by breast cancer cells. The nanostructures, measuring 214.3 nm and 219.3 nm in size, have zeta potentials of −21.6 mV and −20.5 mV, and show improved cellular uptake and stability. Treatment of MCF-7 cells with both formulations resulted in significant inhibition of proliferation, characterised by reduced colony formation, slower wound closure by 48 hours, and decreased spheroid size by days 3 and 6. Apoptosis was confirmed through Annexin V-FITC/PI staining (an elevated Q2/Q3 population) and nuclear fragmentation (Hoechst 33258). These complexes mechanistically triggered hallmark stress responses, which included a loss of mitochondrial membrane potential, increased ROS, and DNA fragmentation associated with histones, all with potencies similar to doxorubicin. At the molecular level, γH2AX, p53, Bax, and PUMA were upregulated, and Bcl-2 and Mdm2 were downregulated, which disrupted mitochondrial homeostasis and led to cytochrome c release. Impaired antioxidant defenses were also evident, with heightened levels of MDA and 4-HNE, and reduced catalase and SOD activity. Metal complexes also downregulated pRb, cyclin D1, and cyclin E, resulting in S-phase arrest without affecting pChk1 or pChk2, and this was similarly observed in MDA-MB-231 cells. Notably, the absence of responses in free Zn(II) complexes highlights the importance of liposomal encapsulation in bioactivity. The results suggest that Zn(II)–liposomal complexes are effective agents capable of targeting multiple pathways involved in cancer cell survival.⁴⁶

Advances in nano-drug delivery systems have underscored the potential of metal complexes, especially ruthenium-based compounds, for the integrated detection and treatment of cancer, known as theranostics. Recently, Siyi Li et al. developed a ruthenium complex (5), which has been altered by the addition of two alkyl chains to produce an amphiphilic molecule (Fig. 3). Using benzaldehyde-capped poly(ethylene glycol) methyl ether (mPEG) via a pH-sensitive benzoic-imine linkage in further PEGylation increased the solubility and responsiveness of the complex to the tumor microenvironment. When co-assembled with phosphatidylcholine (PC), these amphiphilic ruthenium complexes formed liposomes that could encapsulate indocyanine green (ICG), a clinically approved near-infrared photosensitizer, resulting in a multifunctional nanoplatform designated RuPC@ICG. The formulation was engineered to selectively accumulate in tumor cells via a pH-sensitive membrane fusion process, allowing the ruthenium complexes to become embedded in the cell membrane and concurrently deliver ICG into the cell's cytoplasm. This dual-functional system enabled oxygen-sensitive ratiometric imaging, which facilitated early tumour detection, whereas ICG allowed for effective photothermal therapy upon near-infrared irradiation. In vivo research showed substantial accumulation in the tumor, clear imaging capabilities, and effective inhibition of tumor growth with minimal adverse consequences. This work demonstrates that the rational design of amphiphilic, pH-responsive metal complex-based nanocarriers can boost the effectiveness of cancer treatments and improve their diagnostic accuracy, thereby laying the groundwork for the creation of advanced theranostic systems.⁴⁷

Fig. 3 Liposome loaded metal complexes for anticancer therapy.

The study conducted by Gopalakrishnan et al. focused on a ruthenium(II)–p-cymene complex (6) linked with the antibacterial agent trimethoprim, as illustrated in Fig. 3. This compound exhibits both anticancer and antimicrobial activities but is constrained due to its high systemic toxicity, thereby restricting its potential for clinical application. The authors addressed this by creating a liposomal–Ru nanoaggregate incorporating 2-ditetradecanoyl-sn-glycero-3-phosphocholine and 10,12-pentacosadiynoic acid. The π-conjugated poly-diacetylene backbone facilitated the controlled release of drugs under physiological circumstances. In normal kidney cells, this nanoaggregate exhibited decreased toxicity, yet it retained its potency in combating cancer cells of the liver. The nanoaggregate boosted the anticancer effects more than the standalone complex; however, it did not notably enhance the antibacterial properties.⁴⁸

Pancreatic ductal adenocarcinoma (PDAC), with less than 10% 5-year survival rate, remains highly lethal, and gemcitabine, the standard chemotherapy, suffers from poor cellular uptake and resistance issues, and requirement of high doses. Liew et al. developed a synergistic approach by combining a Re(I) bisquinolinyl complex (7), a transition metal-based photosensitizer, with gemcitabine shown in Fig. 3. Encapsulating these two compounds together within liquid crystalline nanoparticles (LCNPs) improved cellular uptake. The encapsulation process yielded high drug loading efficiencies, approximately 70% for gemcitabine and 90% for the Re(I) complex. In vitro release studies revealed that gemcitabine, being hydrophilic, was released more quickly than the lipophilic Re(I) complex. Formulations with a 1 : 1 drug ratio yielded significantly higher anticancer efficacy, as evidenced by IC₅₀ values of 0.15 μM for BxPC3 cells and 0.76 μM for SW1990 cells, achieved through the induction of apoptosis. Research emphasizes the potential of transition metal complexes as complements to chemotherapy and the essential function of nanocarrier systems in improving treatment results against pancreatic ductal adenocarcinoma.⁴⁹

The development of the Co(II) thiosemicarbazone complex and its liposomal formulation loaded with complex 8, as reported by Zhu et al. in 2025, marks a substantial improvement in non-DNA-targeted cancer treatment, addressing the limitations of platinum-based chemotherapy. It exhibited intense toxicity against HepG2 cells, achieving an IC₅₀ value of 9.97 ± 0.44 μM, while outperforming similar complexes and demonstrating a notable dependency on its structure. Particles (∼94.1 nm, PDI = 0.1) with a high entrapment efficiency of 88.2% were obtained through encapsulation into liposomes, resulting in a strong pH-responsive release, with 85% of the content released at pH 4.7 and only 7.6% at pH 7.4, making it suitable for selective delivery to acidic tumor environments. In vivo, it showed a tumor inhibition rate of 79.0%, substantially greater than that of the free complex (54.2%), along with enhanced safety (LD₅₀: 61.10 mg kg⁻¹) and decreased hepatotoxicity. It causes mitochondrial dysfunction marked by a depolarized membrane potential, disrupted cristae, and impaired respiration without interacting with DNA, setting it apart from genotoxic agents. Metabolic flux analysis demonstrated dual inhibition of oxidative phosphorylation and glycolysis, effectively severing the tumour's energy supply. Mitochondrial damage led to the induction of autophagy (increased LC3-II, decreased P62) and immunogenic cell death, characterised by the release of HMGB1, exposure of CRT, dendritic cell maturation (increased CD80/86), and T-cell infiltration. These findings establish liposomal formation of complex 8 as a dual-function agent, combining mitochondria-targeted metabolic disruption with immunomodulation, a developing and promising approach in cancer treatment strategies.⁵⁰

Lipid nanocapsules. Research led by Pierre Idlas et al. examined ferrocifen derivatives like compound P722 within nanocarrier systems. Initial challenges with low drug loading in P722 were addressed through structural modifications, resulting in more effective variants such as P998 and P849 with increased lipophilicity and entrapment efficiency in lipid nanocapsules (LNCs). Formulations 9 and 10 showed gelation characteristics, resulting in the formation of injectable gels shown in Fig. 4. Supramolecular gels created through lone pair–π interactions on the LNC surface introduce a new approach for drug delivery. Gel-based delivery systems have shown effectiveness in treating glioblastoma and metastatic ovarian cancer in living organisms, and they appear to offer potential in managing malignant brain and peritoneal tumors.⁵¹

Fig. 4 Nanogel formation in lipid nanocapsules.

Cubosomes. Cubosomes resemble lipid vesicles similar to those found in liposomes. Amphiphilic lipids are used to form cubosomes with the assistance of a suitable stabilising agent. Since their discovery and classification, self-assembled cubosomes have been employed as active drug delivery systems and have garnered considerable attention and interest. These drug delivery methods include oral, ocular, transdermal, and chemotherapeutic routes. Due to their numerous advantages, the use of cubosomes in drug nanoformulations for cancer treatments is highly promising. These benefits include efficient drug distribution, a substantial surface area, a relatively straightforward manufacturing process, biodegradability, the ability to encapsulate both hydrophilic and hydrophobic compounds as well as amphiphilic substances, targeted release of bioactive agents in controlled way, and biodegradability of lipids.^52,53

Giacomazzo et al. developed complexes of ruthenium(II) with polypyridyl ligands, specifically compound 11 represented in Fig. 5. The synthesised compounds exhibited significant singlet oxygen production, DNA binding capabilities, and high levels of light-activated cytotoxicity against squamous carcinoma cells. Both complexes were successfully encapsulated into monoolein-based cubosomes due to their poor solubility, demonstrating higher encapsulation efficiency and stability. When exposed to light, they efficiently produced intracellular reactive oxygen species, resulting in improved photodynamic therapy outcomes at even low dosages. Cubosomes exhibited stable performance in biological fluids, representing the initial utilisation of ruthenium polypyridyl complex-loaded cubosomes for enhancing biopharmaceutical properties in photodynamic therapy applications.⁵⁴

Fig. 5 Basic structure of cubosome and metal complex used for nano-drug delivery.

Overall, lipid-based nanocarriers, especially liposomes, have demonstrated significant potential in increasing the therapeutic index of metal-based anticancer agents. These systems not only enhance drug stability and bioavailability but also reduce systemic toxicity and improve tumor selectivity. Advancements in research will be driven by strategies like ligand-based targeting, stimuli-responsive release, and supramolecular self-assembly, which are expected to enhance the therapeutic capabilities of these nanosystems in cancer treatment.

Polymer-based nanocarriers

Polymer NPs are formed by modifying natural or synthetic polymers to create submicroscopic particles. The polymer matrix can be tailored to offer specific properties, such as surface chemistry and flexibility. The design and use of the particles can be tailored and applied across various fields. Polymeric nanoparticles have been used to transport medications or genetic material to a targeted location, and they are also used in tissue engineering applications.⁵⁵ Poly(lactic acid) (PLA), chitosan, and poly(ethylene glycol) (PEG) are widely used in the synthesis of polymeric nanocarriers due to their unique properties like biodegradability, and low-toxicity. Specifically, PEG-based nanoparticles offer several benefits, including the ability to be easily modified and their hydrophilic nature, making them particularly well-suited for drug delivery applications.^56,57 The key benefits of polymer-based nanoparticles include their adaptability and compatibility with living tissue, enabling their safe use in medical settings.^58,59

PLA/PLGA-based nanoparticles. Sumit et al. developed two innovative photosensitizers, based on aggregation-enhanced emission (AEE)-active cyclometalated iridium(III) complex 12 in photodynamic therapy (PDT), as illustrated in Fig. 6. Both complexes exhibited increased ROS production, longer lived excited states, intense excitation at 468 nm, and elevated lipophilicity resulting from additional phenyl rings, which enabled easier cell membrane penetration and consequently enhanced cellular uptake, a vital factor for PDT effectiveness. Studies have shown that cytotoxic effects were evident only when light exposure took place following cellular uptake, highlighting the significance of intracellular reactive oxygen species (ROS). To amplify the delivery and therapeutic capabilities, it was encapsulated within PLGA nanoparticles and Soluplus micelles. The Soluplus micelles, approximately 90 nm in size, demonstrated enhanced intracellular delivery and lysosomal localisation capabilities in MCF-7 cell lines, whereas PLGA nanoparticles provided a higher drug loading capacity of 82%. Both formulations improved photoluminescence intensity and excited-state lifetime by limiting internal motion (RIM). Soluplus micelles loaded with the Ir complex exhibited the greatest PDT-induced cell death among tumor cells, underscoring their potential as highly efficient, light-activated anticancer therapies that can be effective even at low doses and with brief irradiation periods.⁶⁰

Fig. 6 Iridium-based metal complexes and nanocarriers used for effective cancer therapy.

A recent study by Das et al. demonstrated the potential of polylactide-co-glycolide (PLGA)-based nanoparticles for the targeted delivery of a taxifolin–ruthenium–p-cymene (TaxRu) complex (13) against lung cancer, as represented in Fig. 7. The TaxRu complex, known for its anticancer activity via inhibition of epithelial–mesenchymal transition (EMT) and angiogenesis, suffered from poor water solubility and oral bioavailability, leading to dose-related toxicity and multidrug resistance. To overcome these challenges, researchers encapsulated TaxRu within PLGA nanoparticles (TaxRu-NPs), ensuring improved solubility, enhanced cellular uptake, and prolonged circulation time. This nanocarrier system enabled passive tumor targeting via the enhanced permeation and retention (EPR) effect, thereby accumulating in the cancerous region and improving therapeutic efficacy. Studies conducted on lung cancer cell lines (A549 and NCI-H460, NSCLC) and benzo[α]pyrene-induced Balb/c mice models demonstrated promising anticancer activity against lung cancer cells, as well as a B(α)P induced lung carcinoma model in mice, by inducing p53/caspase-3 facilitated intrinsic apoptosis events and cell cycle arrest in the sub G0/G1 phase, S phase, and G2/M phase. Furthermore, TaxRu-NPs blocked cancer cell survival, angiogenesis, and invasiveness by inhibiting the VEGF/PI3K signaling pathway and the expression of the EMT biomarker vimentin, thus ultimately eliminating the EMT-mediated metastasis in lung cancer cells. This work highlights the significance of polymer-based nanocarriers in organometallic-based cancer therapeutics and their role in overcoming the limitations of traditional metallodrug formulations.⁶¹

Fig. 7 Polymer-based nano-based metal complexes.

Self-assembled polymer nanoparticles. In 2022, Vinck et al. examined biotin-targeted ruthenium(II) polypyridyl complexes (14) for photodynamic therapy (PDT), with an initial objective of increasing the complexes’ uptake through the SMVT transporter (Fig. 7). The biotin primarily enhanced membrane attachment rather than SMVT-driven uptake into the cell, and it had an adverse effect on the hydrophilic properties of compounds. Notably, these complexes demonstrated aggregation in solutions containing salt, resulting in the formation of “self-assembled” nanoparticles that selectively accumulated in lysosomes, indicating a possible application for lysosome-targeted photodynamic therapy. The complexes exhibited phototoxicity at 670 nm and aggregation-induced emission, despite biotin not being an optimal targeting group, suggesting that they have potential application for lysosome-targeted PDT metal-based photosensitizers.⁶²

Copolymer-based nano-systems. He et al. developed a biodegradable Ru complex (15) containing polymer designed for light-activated combination cancer therapy (Fig. 7). The Ru complex is introduced in which two different therapeutics (the drug and the Ru complex) are rationally integrated and then conjugated to a diblock copolymer (MPEG-b-PMCC) containing hydrophilic poly(ethylene glycol) and cyano-functionalized polycarbonate forming photoresponsive polymeric micelles. These micelles offer high drug loading (97%) and efficient tumor cell uptake in MCF-7 cell lines, and release their anticancer conjugates upon red light irradiation, generating reactive oxygen species (ROS) and significantly inhibiting tumor growth in vivo. The system shows high biocompatibility and biosafety, highlighting its potential as a next-generation multitherapeutic nanoplatform for enhanced phototherapy in cancer treatment.⁶³

PMMA-based nanoparticles. A novel paddlewheel diruthenium complex (16) was developed and synthesized by Coloma et al. by incorporating 5-fluorouracil (5-FU), and it was encapsulated into poly(methyl methacrylate) (PMMA) nanoparticles to enhance anticancer efficacy (Fig. 7). The nanoparticles showed favourable properties and demonstrated potent cytotoxicity against Caco-2 colon cancer cells, with an IC₅₀ value of 6.08 μM, outperforming free 5-FU, especially in drug-resistant cells. The results highlight the synergistic effect of combining 5-FU with the diruthenium core, offering a promising strategy to overcome 5-FU resistance through dual mechanisms of action.⁶⁴

Dendrimer-based nanocarriers. Maciel et al. investigated low-generation nitrile poly(alkylidenamine)-based dendrimers functionalized with the organometallic ruthenium complex (17) as potential anticancer agents (Fig. 7). The generated metallodendrimer exhibited enhanced anticancer activity and specificity, with approximately fourfold lower IC₅₀ values in cancer cell cultures compared to those in non-cancerous cells. The drug loaded dendrimer also displayed minimal hemolysis, a strong affinity for apo-transferrin, having positive zeta potential, and favourable physicochemical properties. Research findings showed that mitochondrial depolarization (thereby producing reactive oxygen species) and the blocking of the cell cycle at the G0/G1 stage all lead to apoptosis and necrosis. In vivo studies demonstrated that it significantly reduced tumor growth in MCF-7 xenograft mice with minimal systemic side effects and a tendency to accumulate preferentially in tumors. Research outcomes indicate the therapeutic benefits of low-generation poly(alkylidenamine)-based dendrimers as safe and effective nanocarriers for ruthenium-based anticancer drugs.⁶⁵

Chitosan-based nanocarriers/nanogels. Pragti et al. created a new nanogel-based drug delivery system that aims to improve cancer treatment by targeting tumors more effectively, releasing the drug in response to unique pH conditions found in tumors, and consequently lowering the risk of side effects and increasing the effectiveness of treatment. These NGs are loaded with glucose ring-conjugated ruthenium(II) arene complexes (18) and (19), which display significant anticancer properties (Fig. 8). The glucose component allows for selective uptake by cancer cells that overexpress GLUT, and biotin–chitosan-based nanoparticles enable dual-targeting through receptor-mediated endocytosis and a pH-triggered release mechanism. The encapsulation of Ru complexes in the nanogel showed substantial increase in their cytotoxic effects towards various cancer cell lines and also amplified their preferential targeting of cancer cells over normal cells. The ruthenium complexes trigger the production of intracellular reactive oxygen species by oxidizing NADH to NAD⁺, resulting in DNA damage and the activation of internal cell death pathways. This approach not only increases the anticancer capabilities of Ru complexes but also provides a cost-efficient and practical system for intelligent drug delivery. The findings emphasize the capabilities of NGs to enhance targeted chemotherapy by facilitating effective cellular absorption and regulated drug delivery (Table 1).⁶⁶

Fig. 8 Chitosan-based nanogel loaded metal complexes in cancer therapy.

Table 1 Overview of polymer-based nanoparticles for delivery of metallic compounds in cancer therapy

Polymer type	Metal compound	Target/application	Ref.
PLGA	Taxifolin–ruthenium–p-cymene	Lung cancer	60
PLGA/soluplus micelles	AEE-active Ir(III) complexes	Breast cancer	61
Self-assembled polymers	Ru(II) polypyridyl complexes	Breast cancer	62
PEG-based copolymer	Ru-containing polycarbonate–drug conjugate	Breast cancer	63
PMMA	Diruthenium-5-fluorouracil complex	Colon cancer	64
Poly-alkylidenamine dendrimers	Ruthenium(II)-cyclopentadienyl complex	Breast cancer	65
Chitosan	Glucose-conjugated Ru(II) arene complexes	Various cancer	66

---

These studies highlight the capabilities of polymer-based nanoparticles in overcoming the conventional therapeutic limitations of metal complexes, including low solubility, drug resistance, and non-specific targeting, by improving the delivery and effectiveness of drugs in cancer treatment.

Inorganic nanoparticles

Gold-based NPs. Gold nanoparticles exhibits exceptional physicochemical attributes, which include biocompatibility, size-dependent optical properties, and ease of functionalization, which makes them promising candidates for developing in the field of drug delivery application.

Watson et al. designed a nanotheranostic platform based on gold nanoparticles (AuNPs) functionalized with luminescent osmium(II) complexes (20), developed for live cell imaging and photodynamically induced therapeutic activity, as illustrated in Fig. 9. The platform involves two sizes of gold nanoparticles (13 nm and 25 nm), which is decorated with an Os(II) complex derived from 1,10-phenanthroline and surface-active bipyridine ligands. These conjugates exhibit strong near-infrared (NIR) luminescence at 785 nm in aqueous solution, enabling deep tissue imaging. The incorporation of AuNPs enhances water solubility and allows efficient delivery and cellular uptake, particularly localizing in the cytoplasmic and perinuclear compartments of lung and breast cancer cells. Upon visible light irradiation at 552 nm, these osmium-decorated AuNPs successfully generate reactive oxygen species (ROS), as confirmed by fluorescence assays and time-resolved luminescence studies, indicating singlet oxygen production. Despite the inherent absorbance of AuNPs and low osmium loading, the system demonstrates clear photodynamic activity, revealing potential as a dual-function imaging and therapeutic agent.⁶⁷

Fig. 9 Different metal complexes used in gold-based nano-drug delivery and its mechanism.

Wang et al. developed self-assembled carrier free Au-based porphyrin nanospheres (AuPNSs) where an Au(III)-tetra-(4-pyridyl) porphyrin (21) serves as the building block, exhibiting high photothermal conversion efficiency (∼48.2%) for photothermal therapy (PTT) (Fig. 9). Modified with a cyclic cRGDfK (cRGD) peptide, the platform exhibits a high binding affinity for integrin receptors, which are generally overexpressed in many types of tumor cells or tumor vessels, but shows limited expression in normal cells, and it exhibited photothermally induced release of the porphyrin monomer from the nanospheres through protonation of the pyridyl groups in the acidic tumor microenvironment. Finally, in vitro ROS- and TrxR-level results revealed that the subsequent release of AuTPyP initiated chemotherapy by inhibition of TrxR activity. Assisted by cRGD modification, the cRGD AuPNSs showed enhanced uptake and synergistic therapy efficiency.⁶⁸

Gold-based nanocomposites have also emerged as a potential drug-delivery platform due to the ease of synthesis, increased surface area, aqueous solubility, biocompatibility, tunability, and a wide range of possibilities for functionalization. Mayank Pal et al. have synthesized Fe(III)–phenolate-based complex 22 as a photochemotherapeutic agent functionalized with a nanocomposite (Fig. 9). The nanocomposite showed significant toxicity in A549 (IC₅₀: 0.006 μM) and HaCaT (IC₅₀: 0.0075 μM) cells after being activated with red light (600−720 nm, 30 J cm⁻²) and demonstrated minimal cytotoxic effects in the dark (>500 μg mL⁻¹). The cytotoxic effectiveness of the nanocomposite (21-AuNPs) against normal human diploid fibroblasts (WI-38) was restricted to an IC₅₀ > 0.053 μM in both dark and red light conditions, suggesting the selective targeting capability of the nanocomposite. The synergic generation of oxygen and hydroxyl radicals from functionalized nanoparticles upon activation with red light was typically responsible for oxidative stress in A549 cells and resulted in disruption to the mitochondrial membrane.⁶⁹

Calcium-based NPs. The calcium ion (Ca²⁺) is a crucial signaling agent that plays a vital role in regulating numerous physiological processes. The significance of Ca²⁺ is now being increasingly recognised in the context of cancer. Multiple studies have shown that Ca²⁺ plays a significant part in tumour formation, cell migration, angiogenesis, and apoptosis.^70,71 The expression of proteins involved in Ca²⁺ signaling in cancerous cells varies significantly from that in normal cells, and the regulation of Ca²⁺ signaling is associated with the development of specific cancers, including breast cancer, colon cancer, lung cancer, liver cancer, and others.⁷² Abnormalities in Ca²⁺ channels directly contribute to cancer development and progression.^73,74 In comparison with normal cells, cancer cells such as breast cancer, prostate cancer, and melanoma exhibit reduced Ca²⁺ influx mediated by stromal interaction molecules to prevent intracellular Ca²⁺ overload, which can cause cell death and promote tumor cell proliferation.

Jinchao Shen et al. developed a combined approach of calcium overload therapy with photodynamic therapy in calcium carbonate (CaCO₃) nanoparticles with calcium ion source loaded iridium complexes (23) having the carboxylic acid moiety on the ancillary ligands which drastically enhanced the drug loading in the NPs (Fig. 10). An overload of calcium levels increases the vulnerability of cells to external stimuli, including reactive oxygen species, Further encapsulation with polyethylene glycol forms IrCOOH–CaCO₃@PEG, prolonging circulation time in the bloodstream is aided by this factor, but it can rapidly degrade in the acidic environment of cancer cells, releasing IrCOOH and excessive calcium ions. IrCOOH–CaCO₃@PEG exhibited a time-dependent cell internalization profile in murine 4T1 breast cancer cells via the endocytosis pathway, indicating that the lysosomes are the primary localization sites of the compounds, showing a 1.7-fold higher therapeutic effect than the blank molecular metal complex. The loaded nanoplatform showed high biocompatibility and a significant inhibition of tumor growth compared to the metal complex when used in a breast cancer-bearing mouse model treated with deeply penetrating two-photon irradiation at a wavelength of 750 nm.⁷⁵

Fig. 10 Calcium carbonate NPs in metal complex delivery to cancer cells.

Silica-based NPs. Silicon dioxide particles, which are commonly known as silica nanoparticles, are formed from the abundant mineral SiO₂ found in rock and sand. These materials are synthesized through a variety of methods, including chemical vapour deposition, hydrolysis, and sol–gel synthesis. Like other nanoparticles, silica nanoparticles with high surface area and chemical stability can be utilized in various adsorption and catalysis applications. In addition to their physical and chemical properties, silica nanoparticles with characteristics like biocompatibility and low toxicity are suitable materials for medical and biological applications including drug delivery, imaging, and tissue engineering.

Karges et al. exploited dual targeting properties: mesoporous silica nanoparticles, which enhance the permeability and retention effect, and the conjugation to folic acid (FA), which acts as a targeting moiety for folate receptor-overexpressed cancer cells, as illustrated in Fig. 11. They have loaded with Ru(II) polypyridine complexes (24) and (25)-functionalized MSNPs for cancer-targeted PDT. The particles without attached FA induced a phototoxic effect upon irradiation at wavelengths of either 480 or 540 nm in a low nanomolar concentration range, without distinguishing between cancerous and noncancerous cells. In contrast to this, nanoformulation with FA did not result in significant cell death when exposed to irradiation in non-cancerous human normal lung fibroblast cells; however, it did cause cell death at concentrations in the low nanomolar range in cancerous human ovarian carcinoma cells. (IC₅₀, 540 nm = 61–187 μg mL⁻¹; 44–50 nM).⁷⁶

Fig. 11 MSNP loaded metal complex in PDT applications.

Carbon-based nanocarriers

Carbon-based nanocarriers consist of 2D materials like graphene, nanotubes, and carbon quantum dots. Because of their superior ability to carry and deliver different medications to living cells, carbon nanoparticles have garnered a lot of attention among various drug delivery systems.⁷⁷ They are superior to all other nanocarriers owing to their versatile physical properties like inherent high surface-area-to-volume ratio for flexibility towards multiple functionalization with different biomolecules, excellent stability, thermal conductivity, high aspect ratio, and cell-membrane penetrating capability, as well as their mitochondria targeting ability. Non-invasive entry into the biological membrane is made easier by their inherent shape. Covalent and non-covalent bonds often bind medicinal molecules to the carbon nanoparticles’ functional walls.⁷⁸

Our recent study showed that the targeted delivery of the Ru(II)N^N complex (26) to MCF-7 breast cancer cells was enhanced using –COOH functionalized multi-walled carbon nanotubes (MWCNTs) (Fig. 12). Biotin, linked via an amine-terminated triethylene glycol (TEG) linker, facilitates SMVT-mediated uptake. Sodium-dependent multivitamin transporters (SMVTs) are overexpressed biomarkers in breast cancer cells and biotin has a keen affinity for SMVT. Cellular uptake studies showed significantly higher internalization in MCF-7 cells (91.53%) compared to HEK 293 cells (13.15%). They show a pH-responsive release mechanism with increased drug release at pH 5.5. Cytotoxicity studies confirmed selective toxicity towards MCF-7 cells, leading to ROS generation, mitochondrial disruption, and G0/G1 cell cycle arrest. This work establishes a promising pH-sensitive nanocarrier system for organometallic cancer therapeutics.⁷⁹

Fig. 12 MWCNT-based nanocarriers for the ruthenium-based complex against breast cancer.

Peptide-based nanocarriers

Peptide-based nanomaterials are viewed as promising candidates for drug delivery owing to their tunable structures, amphiphilic properties, biocompatibility, and enzyme-responsive characteristics. Due to their ability to selectively target affected tissues and regulate the delivery of medications, these agents are considered suitable for cancer treatment.

Recent research utilised four peptide sequences (PD, PK, AD, and AK), which comprised diphenylalanine (FF) motifs, matrix metalloproteinase-9 (MMP-9)-cleavable linkers, and charged segments to encapsulate hydrophobic Au(I)–NHC complexes 27 and 28, as shown in Fig. 13. At low concentrations of less than 1 millimolar, these peptides formed filamentous nanostructures and displayed the ability to circulate for a prolonged period. The peptide nanostructures were found to effectively load drugs, with anionic variants displaying a preference for encapsulating metal-based complexes. Following MMP-mediated cleavage, the nanostructures delivered their contents selectively within the tumor environment. Tests conducted in a lab dish revealed a significant increase in cell toxicity (up to 15 fold in Caki-1 cells and 5 fold in MDA-MB-231 cells) and high selectivity (up to 16-fold) for cancerous cells over non-cancerous cells, due to elevated protease activity in tumors.⁸⁰

Fig. 13 Peptide-based nanocarriers and their mechanism.

This research shows the potential of enzyme-responsive peptide filaments as biodegradable, targeted nanocarriers for metal-based drugs, providing a promising method for targeted cancer treatment.

Protein-based nanoparticles

A few protein-based nanocarriers have been exploited for the targeted delivery of metal complexes for anticancer therapy. Human serum albumin is a major type of nanocarrier that has been extensively studied, while Ferritin-based proteins have been predominantly investigated.

Human serum albumin (HSA). HSA is the most abundant plasma protein and is also a highly promising drug carrier, boasting advantages that include non-toxicity, non-antigenicity, biocompatibility, and biodegradability.^81–83 In the past few years, a number of studies investigating the interaction between medications and HSA have been carried out in depth to assess the binding and transport mechanisms of drugs in the body.^84,85 The HSA–metal drug complex delivery system is a new approach that directly binds metal-based drugs to HSA, which not only prevents metal-based drugs from being destroyed by endogenous molecules during transport in the body but also facilitates the selective accumulation of metal drugs in tumor tissues and targeted release within tumor cells.

To address cisplatin resistance and metastasis in non-small cell lung cancer (NSCLC), Jiang et al. developed Cu(II) complex (29)-loaded HSA nanoparticles using a potent thiosemicarbazone compound (Fig. 14). These nanoparticles, designed to specifically bind to histidine residues (His146/His242) on human serum albumin in a rational manner, enhance targeted delivery and bioavailability. Complex 29 exhibited higher cytotoxicity than its analogues in A549cisR cells, which exhibited resistance to treatment, displaying an IC₅₀ value of 0.59 μM and a resistance factor (RF) of 1.17, which is substantially lower than that of cisplatin (IC₅₀ = 28.78 μM, RF = 3.17), thereby demonstrating its capacity to overcome classical resistance mechanisms. Cu complex 29-loaded nanoparticles demonstrated multitargeted efficacy: they induced apoptosis by depolarising mitochondria, depleting ATP, and producing excessive ROS; they also damaged mitochondrial DNA, exploiting a known vulnerability in drug resistant cells, they suppressed the growth of new blood vessels by reducing VEGF and CD31 levels, and they inhibited metastasis through the modulation of MMP2, MMP9, and VEGFR2. The NPs immunologically reprogrammed tumor-associated macrophages from M2 to M1, thereby strengthening the immune response against tumors without reducing their numbers. In vivo, it resulted in a 65.1% reduction in tumor growth in A549cisR xenografts and they also notably decreased the number of metastatic nodules in the lungs. Studies of the biodistribution confirmed that copper accumulates specifically in tumors causing minimal harm to other parts of the body. Collectively, the multifunctional, mitochondria-targeting, and immunomodulatory characteristics of Cu complex 29 loaded HSA nanoparticles provide a solid foundation for addressing chemoresistance and metastatic progression in non-small cell lung cancer.⁸⁶

Fig. 14 Various metal complex loaded human serum albumin protein NPs and their in vivo advantages.

To improve the efficacy and targeting of platinum-based cancer drugs, Yang et al. developed a HSA-based nanoparticle system loaded with a potent Pt(II) agent (30) (Fig. 14) A platinum(II) thiosemicarbazone nanoplatform anchored to human serum albumin (HSA) offers a promising approach to cancer treatment that involves targeting cancer cells specifically and modifying the surrounding microenvironment. Designing ligands with leaving groups allowed the synthesis of Pt(II) complexes that have greater selectivity and reduced off-target toxicity, with Pt(II) complex 30 being the most promising compound (IC₅₀ = 5.86 μM, SI = 4.22). The cytotoxicity of Pt coordination compounds is lower than that of free ligands, partly due to decreased metal ion chelation; however, they exhibit improved pharmacokinetics and lower normal cell toxicity. Research on human osteosarcoma 143B cells and normal human liver HL-7702 cells conducted in vitro showed that these complexes were preferentially taken up by cancer cells, which were more susceptible to their cytotoxic effects, while showing exhibiting minimal toxicity to healthy cells. Structural analyses confirmed a stable, site-specific complex between HSA and 30, where the His242 residue substitutes the chloride ligand, securing the Pt center within albumin's IIA subdomain. The resultant nanoparticles, approximately 85 nm in size and with a surface charge of −28.7 millivolts, showed notable pH sensitivity, releasing approximately 83% of their platinum content under acidic conditions, mimicking a tumor environment (pH 4.7), and maintaining structural integrity in normal physiological pH. In vivo, the nanoparticles substantially outperformed both free complex and ligand in terms of tumour inhibition, with inhibition percentages of 73.9%, 56.8%, and 45.2%, respectively, without causing systemic toxicity. The NPs triggered both apoptosis and autophagy in 143B cells, as evidenced by mitochondrial cytochrome c release, caspase activation, and LC3-II upregulation with p62 degradation. Additionally, potent antiangiogenic activity was observed via CAM assays and reduced VEGF/CD31 expression, implicating a multifaceted interplay between cell death and angiogenesis suppression. Collectively, the HSA–Pt complex (30) nanoparticle system exemplifies a promising translational candidate that leverages albumin-mediated delivery and multi-pathway tumor suppression to enhance therapeutic outcomes in osteosarcoma and potentially other solid tumors.⁸⁷

To combine cancer diagnosis and therapy, Zhang Z et al. developed a novel indium (In)-based fluorescent compound (31) with strong cytotoxicity and loaded it into human serum albumin nanoparticles (Fig. 14). These nanoparticles showed enhanced bioimaging capabilities and anticancer activity compared to the free compound. In vivo, they effectively induced autophagy, apoptosis, and inhibited the PI3K–Akt signaling pathway, demonstrating their potential as a powerful theranostic platform for cancer treatment.⁸⁸

A novel Pt(II) thiosemicarbazone compound, 32, showed potent anticancer effects, particularly against cisplatin-resistant SKOV-3/DDP cells, with an IC₅₀ value of 4.23 ± 0.75 μM and a low resistance factor of 1.09, suggesting minimal cross-resistance and high therapeutic potential. Of note, 32 had the highest selectivity index (SI = 3.28) among the series tested, highlighting its favorable cytotoxicity profile toward cancer cells compared to normal cells. 32 was co-loaded with indocyanine green (ICG) into human serum albumin nanoparticles to improve delivery and combine therapeutic approaches, resulting in uniform spherical particles with a size of approximately 122 nm, a high ICG encapsulation efficiency of 88.6%, and excellent colloidal stability. The nanoformulation exhibited pH-responsive and laser-enhanced release properties, with approximately 5% of 32 released at a pH value of 7.4 compared to approximately 83% at a pH value of 4.7, and this increased to approximately 91% under 808 nm laser irradiation. In vivo fluorescence imaging in SKOV-3/DDP tumor-bearing mice revealed a 7-fold higher tumor accumulation of 32 than free ICG at 18 h post-injection, with minimal off-target distribution. Photothermal evaluation showed that 32 increased tumor temperature by 19 °C upon laser exposure, exceeding the 13 °C increase observed with free ICG. Antitumor efficacy studies demonstrated a tumor inhibition rate of 90.7% for ICG@HSA-(32) NPs + laser, 19.5% for cisplatin, and 57.0% for 32 alone. Furthermore its nanoformulation induced caspase-3/GSDME-mediated pyroptosis, as evidenced by increased cleaved-GSDME and caspase-3 expression, accompanied by elevated LDH and ATP leakage. Moreover, they triggered immunogenic cell death (ICD), as reflected by enhanced calreticulin and HMGB1 expression, increased TNF-α and IL-6 secretion, reduced IL-10 levels, and elevated CD8⁺/CD4⁺ T-cell infiltration in tumors. Toxicological assessments revealed a higher LD₅₀ value for ICG@HSA-(32) NPs (41.17 μmol kg⁻¹) than free 32 (29.15 μmol kg⁻¹) and minimal impact on organ histology, body weight, and serum biomarkers. Collectively, these data establish ICG@HSA-(32) NPs as a highly effective and safe nano-therapeutic platform that integrates chemotherapy, PTT, and immunotherapy to overcome cisplatin resistance via pyroptosis and immune activation.⁸⁹

Ferritin (FRT) protein. Ferritin is comprised of 24 subunits and consists of two subtypes: light chain FRT (LFn) and heavy-chain FRT (HFn).⁹⁰ The FRT protein has the ability to naturally self-assemble into a hollow, spherical structure,⁹¹ featuring an internal cavity which serves as an effective template for the production of monodisperse and highly crystalline nanoparticles.⁹² The FRT architecture can degrade in an acidic environment but can be largely restored when the pH conditions return to physiological levels.^93–95 The distinct properties of FRT render it an excellent and potent nanoplatform for building multifunctional nanoparticles that can be used for imaging and drug delivery purposes.^96,97 Studies have demonstrated that HFn preferentially interacts with cancer cells that exhibit increased expression of the transferrin receptor (TfR1), enabling it to focus on and visualise tumour tissue.^98–100

Tang et al. introduced a multifunctional nanoplatform that combines ferroptosis and photodynamic therapy (PDT) for enhanced breast cancer treatment (Fig. 15). The system uses a tumor-targeting ferritin carrier to deliver Zn-complex (33), a molecule formed from zinc porphyrin and benzaldehyde nitrogen mustard, which acts in both photo- and chemodynamic therapy. Upon 660 nm laser irradiation, it generates toxic ROS through PDT and a Fenton-like reaction, leading to lipid peroxide buildup, glutathione depletion, and GPX4 downregulation, effectively inducing ferroptosis. This approach enhances ROS accumulation in the tumor microenvironment, offering a promising strategy for safer and more effective cancer therapy.¹⁰¹

Fig. 15 Ferritin-based nanocarriers for cancer therapy.

Apoferritin. Research has shown that apoferritin (AFt), the non-coordinated form of ferritin, is capable of encapsulating and releasing small molecules in response to pH changes.^102–104 Additionally, the protein adducts formed through this encapsulation process exhibit good biocompatibility and high stability under physiological conditions. The high demand for nutrients during tumor growth and the overexpression of ferritin receptors on tumor cell surfaces suggest that AFt could be utilized as a targeted delivery system for cancer treatment. To address the rising issue of multidrug-resistant cancers,⁹⁵ Xiong et. al. developed apoferritin-encapsulated copper polypyridine complex (34) nanoparticles (AFt-Cu) as a novel chemotherapeutic strategy shown in (Fig. 16). These nanoparticles showed high water solubility and primarily accumulated in the cytoplasm with enhanced cellular uptake, and potent cytotoxicity against drug-resistant cancer cells, while being less toxic to healthy cells. Mechanistic studies revealed that AFt–Cu triggers autophagy-dependent apoptosis, involving LC3, p62, and caspase 8 pathways. In vivo studies in a mouse model of multidrug-resistant colon cancer demonstrated significant tumor growth inhibition, highlighting apoferritin's ability to act as a natural nanocarrier for targeted cancer therapy.¹⁰⁵

Fig. 16 Cu-complex loaded apoferritin NPs for effective cancer therapy.

In 2024, Man and co-workers presented a multifunctional nanoplatform based on a tetranuclear Cu(I) complex (35) (Fig. 17) encapsulated in apoferritin (AFt-(35) NPs), which provides a dual-mode cancer therapy approach that combines cuproptosis and in situ bioorthogonal catalysis. The rationale is based on Cu(I)'s higher catalytic activity and its ability to induce cuproptosis compared to Cu(II), as well as the anticancer properties of thiosemicarbazone ligands. It exhibited a high level of toxicity against cancer cells (IC₅₀: 0.86–2.32 μM) and showed a notable selectivity of about 3 in SKOV-3 ovarian cancer cells. The encapsulation of apoferritin led to the formation of uniform nanoparticles with a zeta potential of approximately 23.6 mV and an encapsulation efficiency of 81.2%. These nanoparticles demonstrated excellent serum stability and a pH-responsive release of 35, with a release rate of 87% at pH 4.7 compared to 8% at pH 7.4, which facilitates lysosomal release within tumor cells. Experiments confirmed that (35) and AFt-(35) nanoparticles trigger cuproptosis, characterised by the loss of mitochondrial membrane potential (JC-1 shift), a decrease in FDX1 and LIAS expression, and DLAT protein aggregation. Notably, Cu₄ catalysed the in situ formation of a cytotoxic resveratrol analogue (compound 3) from azide and alkyne precursors via copper-catalysed azide–alkyne cycloaddition (CuAAC) inside cells, thereby enhancing therapeutic efficacy. In vivo, AFt-(35) nanoparticles significantly reduced tumor volume, which also exhibited minimal off-target toxicity, with an LD₅₀ value of 38.0 μmol kg⁻¹. The treatment also triggered robust immunogenic cell death (ICD), characterised by increased CRT exposure, HMGB1 and ATP release, dendritic cell maturation, and enhanced CD4⁺ and CD8⁺ T cell infiltration. Significantly, in a bilateral tumor model, systemic immune responses were confirmed, resulting in a distant tumor inhibition rate of ∼44.7%–47.9%, thereby validating the immunomodulatory properties of this nanoplatform. Overall, this research combines copper-mediated catalysis and cancer immunotherapy, establishing Aft-(35) NPs as a promising platform for synergistic chemo-immunotherapeutic treatment via cuproptosis and in situ chemical activation.¹⁰⁶

Fig. 17 Ferritin-based nano-metal complexes for cancer therapy.

Researchers led by Xu et al. in 2024 successfully encapsulated a mitochondria-targeted arene Ru(II) thiosemicarbazone complex (36) (Fig. 17) into apoferritin nanocages (36-AFt NPs), thereby overcoming therapeutic limitations in triple-negative breast cancer (TNBC) and improving both tumor targeting and safety. The resulting nanoplatform displayed advantages including uniform spherical shape (∼11.6 nm), stability in serum, and a drug release mechanism that responds to pH levels (∼85% at pH 4.7), paired with selective cytotoxicity in TNBC cells through transferrin receptor-mediated uptake. In vivo, (36)-AFt NPs performed better than free 36, with higher biosafety (LD₅₀ = 70.94 μmol kg⁻¹), 69.3% tumor growth inhibition, and reduced metastasis, indicating increased tumor accumulation and minimal systemic toxicity. The formulation disrupted mitochondrial homeostasis through mechanisms that involved membrane depolarization (47.5%), increased levels of mitochondrial ROS, and mt-DNA damage, ultimately resulting in suppressed oxidative phosphorylation (OXPHOS) without impacting non-mitochondrial respiration. (36)-AFt NPs also induced ferroptosis, which was characterized by a decreased GSH/GSSG ratio, enhanced lipid peroxidation, and downregulation of GPX4 and SLC7A11. A significant breakthrough was the activation of the cGAS–STING pathway by mtDNA leaking into the cytosol, leading to STING–TBK1–IRF3 signaling and the systemic release of IFN-α. The treatment immunologically repolarized macrophages towards an M1 phenotype (characterized by an increase in CD86 and a decrease in CD206), increased T-cell infiltration (including CD4⁺ and CD8⁺ T-cells) and elevated levels of proinflammatory cytokines (IFN-γ, IL-6, and TNF-α), ultimately contributing to an immunostimulatory tumor environment. This nanoplatform, therefore, combines mitochondrial damage, ferroptosis initiation, and activation of both innate and adaptive immunity, providing a promising approach to targeted treatment of triple-negative breast cancer.¹⁰⁷

A nanotherapeutic strategy in 2024 by encapsulating a rationally optimized Rh(III) thiosemicarbazone complex, 37, (Fig. 17) within apoferritin (AFt) nanocages was proposed by Li et al., to overcome the intrinsic limitations of metal-based chemotherapeutics. The AFt-(7) NPs demonstrated improved physicochemical stability, targeted delivery to cancer cells, and significant toxicity towards multidrug-resistant A549/ADR NSCLC cells (which showed an IC₅₀ value of 2.92 μM, compared to 5.33 μM for the free complex (37)), without harming normal cells. The nanoparticles exhibited pH-responsive release characteristics, with approximately 81.5% of 37 being released under acidic conditions mimicking the tumor environment, thereby confirming their potential for targeted delivery to tumors. In vivo, AFt-(37) NPs yielded a 71.1% tumor inhibition rate, outperforming both cisplatin and unencapsulated 37 without inducing detectable systemic toxicity, as shown by intact organ function, stable body weight, and unchanged hepatic and renal markers. Mitochondrial dysfunction, oxidative stress, and apoptosis were initiated in AFt-(37) NPs, occurring through the mitochondrial pathway, including Bax/Bak upregulation, cytochrome c release, and caspase-3 cleavage. They also triggered lethal mitophagy, which was indicated by the conversion of LC3-II, increased levels of PINK1/Parkin, and disrupted autophagic flux, with 3-MA reversing cytotoxicity, showing that mitophagy contributed to cell death. Beyond direct cytotoxicity, the nanoplatform induced immunogenic cell death through CRT exposure, HMGB1 release, and ATP secretion, accompanied by dendritic cell maturation (increased CD80/86), thus facilitating antitumor immune priming. In addition, metabolic profiling showed that both oxidative phosphorylation and glycolysis were suppressed, ultimately leading to energy starvation and AMPK activation. The combined inhibition of energy metabolism and the repolarization of tumor-associated macrophages (characterized by decreased CD206, increased TNF-α, and decreased IL-10) led to a reversal of the immunosuppressive tumor environment and facilitated the entry of CD4⁺/CD8⁺ T cells, along with an increase in pro-inflammatory cytokines (IL-1β and IFN-γ). Together, AFt-(37) NPs constitute a complex nanotherapeutic approach that combines chemotherapy, immunotherapy, and metabolic targeting, providing a promising framework for overcoming drug resistance and enhancing NSCLC treatment outcomes.¹⁰⁸

Man et al. in the year 2024 developed (38)@AFt nanoparticles, which represent a significant step forward in multifunctional cancer theranostics by combining diagnostic and therapeutic capabilities into a single, cancer-targeted nanoplatform. The hetero-trinuclear Gd(III)–Cu(II) complex, 38, (Fig. 17) comprising 8-hydroxyquinoline-2-carboxaldehyde-thiosemicarbazone, is rationally designed for encapsulation within apoferritin nanocages, achieving an encapsulation efficiency of 73.5% and a hydrodynamic diameter of approximately 24 nm. This enables dual-modal imaging via Magnetic Resonance Imaging (MRI) and Photoacoustic Imaging (PAI), selective chemotherapy, mild photothermal therapy, and immune activation. Studies comparing mononuclear Gd(III) complexes revealed that 38 was more potent, and it exhibited selective cytotoxicity, and provided increased imaging contrast with an r₁ value of 4.81 mM⁻¹ s⁻¹, while having an IC₅₀ value of 0.58 μM in 4T1 cells. Apoferritin encapsulation did more than just facilitating targeted delivery and pH-responsive drug release (87.9% at pH 4.7), it also greatly enhanced kinetic inertness and in vivo biosafety (Gd release <0.06% over 48 hours). 38 disrupted both glycolysis and oxidative phosphorylation, leading to energy collapse and apoptosis (34.4% with NIR), and triggered immunogenic cell death through the exposure of calreticulin and release of HMGB1. Immune activation triggered a cascade that led to dendritic cell maturation, infiltration of CD4⁺/CD8⁺ T cells, and systemic tumor suppression in bilateral models. Collectively, these findings establish (38)@AFt NPs as a robust nanotheranostic platform, validated by its mechanism of action, offering a synergistic form of multimodal cancer therapy with high selectivity, precise imaging, and immunostimulatory efficacy.¹⁰⁹

A comprehensive investigation by Man et al. in the previous year, 2023, of Gd(III)-based thiosemicarbazone complexes (39) (Fig. 17) for cancer theranostics revealed that the rational design, mechanistic insight, and preclinical evaluation of four distinct complexes (C1–C4) showed a strong correlation between structure and activity, with N4-substitution significantly increasing the cytotoxicity and selectivity. The dimethyl-substituted complex (39) stood out as the primary candidate due to its potent cytotoxicity, with an IC₅₀ value of 8.8 ± 0.53 μM against HepG2 cancer cells, minimal toxicity toward normal liver cells, and a high thermodynamic stability constant (log K = 24.6). Additionally, encapsulating the complex within apoferritin (AFt-(39) NPs) improved its therapeutic profile, enhancing colloidal stability, tumor selectivity, and pH-triggered release, which reached approximately 86% at pH 4.7, without compromising metal–ligand integrity, as evidenced by less than 0.1% Gd release in the serum. Studies of MRI relaxivity showed that the compound provided comparable T₁-weighted contrast (r₁ = 3.3 mM⁻¹ s⁻¹), and in vivo imaging of mice with tumors revealed greater enhancement of tumor-specific signals. Therapeutically, AFt-(39) NPs resulted in a 77.4% tumor inhibition rate with minimal systemic toxicity, as confirmed by histopathology and blood biochemistry assessments. In a mechanistic sense, both 39 and its nanoformulation caused both apoptosis (with 38.4% apoptotic cells in vitro) and ferroptosis, which were characterised by lipid peroxidation, downregulation of GPX4, and the generation of ROS, and also triggered immunogenic cell death. Activation of dendritic cells and increased infiltration of CD8⁺/CD4⁺ T cells in living organisms confirmed the dual cytotoxic–immunomodulatory effects of the treatment. These findings collectively position AFt-(39) NPs as a multifunctional theranostic platform providing targeted cancer treatment, imaging capabilities, and simultaneous anticancer mechanisms via ferroptosis, apoptosis, and immune system activation.¹¹⁰

Lactoferrin. Lactoferrin (LF) is a natural glycoprotein belonging to the transferrin family, predominantly found in mammalian milk.^111,112 Notably, lactoferrin plays a key role in iron transport within the body, while also exhibiting antibacterial, antiviral, antioxidant, and antitumorigenic properties.^113–116 Because of its high biocompatibility, ability to break down biologically, and tolerance within the body, LF has been developed as an active therapeutic agent and drug delivery vehicle.

Researchers, in a concerted effort, developed multifunctional metal-based anticancer agents in 2022 by demonstrating potent and multimodal anticancer activity through Ga(III) isopropyl-2-pyridyl-ketone thiosemicarbazone complexes, particularly, 40 (Fig. 17) and its lactoferrin nanoformulations (LF-(40) NPs). Modifications to the N4 position of compounds increased their cytotoxic effects, and the (40) variant showed a low IC₅₀ value of 1.05 ± 0.07 μM against MCF-7 cells, outperforming its analogues and control treatments that were not attached to a ligand. Incorporating drugs into LF-(40) nanoparticles resulted in stable spherical particles approximately 33.6 nanometers in size, with an encapsulation efficiency of 88.9% and a drug release mechanism that is triggered by acidic environments, such as those found in tumors. Studies of the mechanism showed that selective tumor targeting, intracellular lysosomal localization, and increased accumulation within the body in living organisms all contributed to superior tumor growth inhibition, amounting to 73.8% compared to 52.1% for free 40. Notably, the LF-(40) NPs decreased systemic toxicity, thereby conserving liver and kidney function, and preventing the weight loss or mortality seen with free 40. Moreover, both free 40 and LF-(40) NPs triggered caspase-3-mediated apoptosis, ferroptosis through the production of ROS, disruption of mitochondria, and downregulation of GPX4, as well as T cell-mediated immune activation, as shown by increased CD4⁺/CD8⁺ infiltration and PD-1 upregulation. The anti-angiogenic effects were confirmed by suppressing CD31, VEGF, and HIF-1α. Overall, these findings demonstrate that LF-(40) NPs have the potential to be a valuable tumor-targeted nanoplatform that utilizes apoptosis, ferroptosis, immune modulation, and angiogenesis inhibition to achieve high therapeutic efficacy with minimal toxicity (Table 2).¹¹⁷

Table 2 IC₅₀ values (μM) of protein loaded metal complexes

Nanocarrier	Metal complex	Cell lines	Blank metal complex vs. nano metal complex IC50 values (μM)
Human serum albumin	Cu(II)2-hydroxy-3-methoxybenzaldehyde thiosemicarbazone compounds (29)	A549	0.26 ± 0.05/0.14 ± 0.05
		A549cisR	0.29 ± 0.11/0.15 ± 0.04
		HL-7702	1.08 ± 0.20/1.15 ± 0.33
Human serum albumin	Di-2-pyridone ketone-4,4-dimethyl-thiosemicarbazone-Pt(II)-chlorine (30)	143B	5.86 ± 0.23/3.17 ± 0.16
		Lovo	9.22 ± 0.71/6.03 ± 0.37
		A375	8.24 ± 0.81/5.72 ± 0.31
		HL-7702	25.32 ± 1.37/>40
Human serum albumin	In(III) quinoline-2-formaldehyde thiosemicarbazone compounds (31)	A549 cells	0.76 ± 0.08/0.36 ± 0.0
Human serum albumin	Pt(II) pyridine-2-formaldehyde thiosemicarbazone com pound (32)	SiHa	4.49 ± 0.62/3.85 ± 0.74
		SiHa/DDP	6.73 ± 0.76/5.54 ± 0.75
		SKOV-3	3.89 ± 0.84/3.11 ± 0.46
		SKOV-3/DDP	4.23 ± 0.74/3.28 ± 0.53
		HOSE	13.86 ± 0.68/12.45 ± 1.24
Ferritin	Zinc porphyrin (ZPP) and benzaldehyde nitrogen mustellate (33)		—
Apoferritin	Cu(II) complex with a 4′ phenyl-2,2′:6′,2′′-terpyridine ligand (34)	A549, A549R, SW620, SW480, HeLa, SGC7901, HepG2, and SW620 AD300	2.13–5.49
		HK2	20.35 ± 1.9
		HEK293T	23.26 ± 2.33
		L02	13.87 ± 2.39
Apoferritin	Tetranuclear Cu(I) complex (35)	MDA-MB-468	2.32 ± 0.45/1.23 ± 0.22
		A549	1.73 ± 0.37/0.89 ± 0.09
		SKOV-3	0.86 ± 0.12/0.41 ± 0.07
		HK-2	2.61 ± 0.37/2.82 ± 0.48
		WRL68	2.44 ± 0.52/2.56 ± 0.45
Apoferritin	1,10-Phenanthroline-2,9 diformaldehyde thiosemicarbazone Ru(II)complexes (36)	MDA-MB-468	12.71 ± 1.03/8.03 ± 0.81
		BT-20	12.33 ± 1.75/8.85 ± 0.65
		MDA-MB-231	10.36 ± 1.45/6.11 ± 0.79
		MCF-10A	41.32 ± 1.36/>50
Apoferritin	Rh(III) 2-benzoylpyridine thiosemicarbazone complexes (37)	A549	5.21 ± 0.82/2.89 ± 0.76
		A549/ADR	5.33 ± 0.68/2.92 ± 0.48
		WI-38	17.88 ± 1.42/23.36 ± 2.04
Apoferritin	Gd(III)–Cu(II) 8-hydroxyquinoline-2-carboxalde hyde-thiosemicarbazone complex (38)	4T1	0.58 ± 0.19
		AML12	1.79 ± 0.75
Apoferritin	Gd(III) 8-hydroxyquinoline 2-carboxaldehyde-thiosemicarbazone complexes (39)	A549	11.0 ± 0.18/7.2 ± 0.86
		143B	13.1 ± 0.62/8.5 ± 0.93
		HepG2	8.8 ± 0.53/5.3 ± 0.62
		MCF-7	17.9 ± 1.17/12.7 ± 0.52
		HeLa	13.5 ± 0.96/10.4 ± 0.64
		HL-7702	34.5 ± 2.24/41.8 ± 1.69
Lactoferrin	Ga(III) isopropyl-2-pyridyl-ketone thiosemicarbazone compounds (40)	MCF-7	1.05 ± 0.07/0.81 ± 0.09
		NCI-H929	5.57 ± 0.48/4.65 ± 0.44
		HCT-116	6.83 ± 0.51/5.28 ± 0.43
		WI-38	5.19 ± 0.46/8.03 ± 0.33

---

Hybrid nanoplatforms

Hybrid nanoparticles are made up of distinct components, including organic–inorganic, metal–polymer, or core–shell configurations, engineered to integrate multiple functions within a single platform. These multi-purpose systems are becoming more commonly used in cancer treatment because they have improved stability, targeted delivery, and controlled release capabilities.

Zhang et al. designed a new type of metal–phenolic network nanoparticle system (PFS-NPs) that responds to glutathione, which aims to boost the effectiveness and immunogenicity of cisplatin-based chemotherapy. These nanoparticles are made up of a modified cisplatin prodrug (41), a polyphenol with amphiphilic properties and disulfide bonds, and Fe³⁺ ions (Fig. 18). They release active components in response to signals from the tumor microenvironment, such as low pH levels and high glutathione levels. Upon being internalized, glutathione (GSH) triggers the conversion of cisplatin into its toxic form and disrupts the balance of redox reactions, resulting in the production of reactive oxygen species (ROS) via the Fenton reaction. The cascade triggers immunogenic cell death in 4T1 cells, characterised by the exposure of CRT, release of ATP, and secretion of HMGB1. In vivo, PFS-nanoparticles display significant antitumor properties, stimulate an immune response (increased levels of IFN-γ and TNF-α), induce dendritic cell maturation, facilitate CD8⁺ T cell infiltration, and suppress immunosuppressive regulatory T cells (Treg). Experiments involving tumor rechallenge demonstrated the presence of long-term immunological memory. The research introduces a nanoplatform that is compatible with living tissues, integrating chemotherapy with immunotherapy as a potential approach for advanced cancer management.¹¹⁸

Fig. 18 Hybrid NP loaded metal complexes.

A nanodelivery platform responsive to near-infrared light was introduced by Nsubuga et al. This platform is capable of being activated by light and is designed for precise and efficient cancer treatment and diagnosis. The system comprises 10 nm NaGdF₄:Nd/Yb/Tm upconversion nanoparticles coated with a thin mesoporous silica shell that is functionalized with photo-switchable azobenzene molecules. The nanoparticles were loaded with the DNA-intercalating ruthenium complex (42) and released upon exposure to near-infrared (NIR) excitation (Fig. 18). Nd³⁺ ions absorbed NIR light, which was then converted into UV and visible emissions by Tm³⁺ activators, resulting in the reversible trans–cis isomerization of azobenzene and controlled release of the drug. Efficient delivery of molecules into cells and their targeting to the nucleus were accomplished with relatively low levels of energy density (<1 W cm⁻²) and brief exposure periods. This advanced delivery system has numerous benefits, such as extremely compact dimensions, rapid cellular uptake, effective deep-tissue penetration, and live monitoring of drug delivery. Future research efforts will focus on modifying nanoparticles with ligands that specifically target tumors to enhance their ability to target these sites. The proposed platform appears to hold considerable potential for developing photoactivatable and nucleus-targeted treatments for deep seated tumors.¹¹⁹

Hybrid mesoporous silica nanoparticles were developed by Kundu et al. and were modified with chitosan and biotin, which were connected using polyethylene glycol, as part of one study to target delivery of cancer drugs specifically to cancer cells. Biotin was selected due to its capacity to bind selectively to ανβ3 integrin receptors that are overexpressed on cancer cells, thereby promoting receptor-mediated endocytosis. Chitosan acts as a pH-sensitive barrier, allowing for the controlled release of drugs in the acidic environment found in tumors, thereby minimizing the premature leakage of drugs under normal physiological conditions. Novel azide-bridged zinc Mannich base complexes (43), were incorporated into these hybrid nanocarriers to boost their therapeutic potential represented in Fig. 18. These complexes were able to produce an excess of reactive oxygen species (ROS), resulting in DNA damage and apoptosis in cancer cells. Loaded with 43, the hybrid nanoparticles showed significant cell-killing activity against a range of cancer cell types revealing greater selectivity between cancer and normal cells than the unattached (43) complexes. The synergistic effects resulted in a substantial enhancement of the anticancer efficacy and selectivity of 43, demonstrating the potential of hybrid nanoparticles as intelligent drug delivery systems for precision oncology.¹²⁰

Ishaniya and fellow workers explored a drug delivery platform for organoruthenium complex [Ru(η6-p-cymene)(piperlongumine)(Cl)], (44), derived from the natural anticancer agent piperlongumine (Fig. 18). The researchers used mesoporous silica nanorods (MSNRs) to overcome the inherent drawbacks of metallodrugs, specifically their low solubility, restricted bioavailability, and brief systemic circulation. The MSNRs were modified with a polydiacetylene–lipid (PL) mixture of PCDA and DMPC, which not only stabilized the drug but also provided red fluorescence and sustained release capabilities through ene–yne conjugation. The nanoformulation showed a controlled and prolonged release of the (44) complex under various conditions, including physiological and cancerous ones, thereby preventing uncontrolled leakage. Cellular studies found that the nanoformulation was more effective at fighting cancer, resulting primarily in cell death through apoptosis and a significant slowdown of the cell cycle's G0/G1 phase in MCF-7 and THP-1 cells, whereas free complex (44) caused necrotic effects. Despite observing a decrease in antioxidant effectiveness following encapsulation, which can be attributed to interactions with the nanocarrier, the treatment's benefits still outweigh this disadvantage. This study represents one of the initial reports to employ a PL-coated MSNR system for organoruthenium delivery, providing dual modality capabilities, comprising therapeutic and diagnostic applications through fluorescence emission. The study presents a promising approach to improve the stability, targeting ability, and effectiveness of metallodrugs against cancer through the rational design of nanocarriers.¹²¹

Wang et al. developed a cyclometalated Ir(III) complex–porphyrin conjugates (45) as advanced photosensitizers (PSs) for photodynamic therapy (PDT) (Fig. 18). To overcome the short-wavelength absorption limitations of traditional Ir(III) complexes, the authors developed mono and tetra-nuclear conjugates that self-assemble into carrier-free nanoparticles (NPs) without auxiliary agents. These NPs exhibit long-wavelength absorption in the near-infrared region, enabling deeper tissue penetration and reduced photodamage to normal tissues. Notably, tetranuclear conjugate (45) NPs demonstrate aggregation-induced emission (AIE) characteristics, high singlet oxygen (¹O₂) generation, potent phototoxicity, good biocompatibility, and excellent cellular uptake under white light. The combination of porphyrin and Ir(III) units enhances both the photophysical and therapeutic properties, positioning these PS-loaded NPs as promising candidates for effective and clinically translatable PDT in cancer treatment.¹²²

Wei et al. proposed employing biotin-modified Iridium(III)-based coordination polymer (46) nanoparticles to increase both the potency and precision of photodynamic therapy (PDT) (Fig. 18). The method is often unsuccessful due to poor targeting by most photosensitizers and the antioxidant power of cancer cells that minimizes damage by ROS. In this approach, the authors created a system that simultaneously targets tumors and accumulates in the mitochondria. The uptake of biotin-attached Ir-complex NPs in A549 cells was higher than that in other cells and they were found mostly in the mitochondria. Once the nanoparticles were exposed to light (for 15 minutes and with 400 nm wavelength and 10 mW cm⁻² intensity), they produced singlet oxygen which led to oxidative stress, damaged the mitochondria and stimulated both apoptosis and ferroptosis. The results of these studies pointed to a decline in intracellular antioxidants NADPH and GSH, reduced MMP, shortage of ATP, activation of Caspase-3, increased LPO and decreased GPX4. Researchers found that 46 had an impressive cancer-targeting effect and therapeutic results in living mice, as demonstrated by a decrease in tumor growth after being exposed to light. This aims to design a single system combining both targeting, imaging and therapy in one unit. The addition of mitochondrial targeting and management of redox balance greatly benefits the outcomes of PDT. These types of Ir-complex-based NPs have the potential to be used as next-generation photosensitizers for treating cancer (Table 3).¹²³

Table 3 Hybrid nanoparticle systems for targeted cancer therapy

Type of hybrid nanoparticle	Metal complex	Mechanism/trigger	Therapeutic advantage	Ref.
Metal-phenolic network nanoparticles	(41)	Tumor microenvironment (GSH, low pH), Fenton reaction	ROS-mediated immunogenic cell death, immune activation, long-term memory response	118
Photo-responsive upconversion hybrid system	(42)	NIR light-induced photolabile benzonitrile ligand was cleaved, resulting in the drug release	Range of NIR absorption (808 or 980 nm), 90% MCF-7 cell death after 20 min NIR (0.65 W cm^−2), light-triggered nuclear delivery	119
Organic–inorganic hybrid nanoparticles	(43)	pH-Responsive release (acidic tumor), receptor-mediated uptake	ROS generation, controlled drug release(pH ≈ 5), IC50 values ranging from 6.5 to 28.8 μM through induction of apoptosis	120
Polydiacetylene-lipid coated mesoporous silica nanorods	(44)	Stable under physiological pH, controlled release	Sustained delivery, fluorescence-based tracking, enhanced apoptosis	121
Carrier-free self-assembling organic nanoparticles	(45)	Light-responsive (500–700 nm) PDT	AIE properties, deep penetration, (IC50 ≈ 0.47 μM)	122
Carrier-free self-assembling polymer nanoparticles	(46)	Light irradiation (400 nm, 10 mW cm^−2, 15 min) triggers ^1O2 generation	It targets the tumor and mitochondria, promotes death in several ways by apoptosis and ferroptosis and increases ROS levels	123

---

Challenges in NDDs in metal complex-based cancer therapy

Cancer treatments based on metal complexes have demonstrated considerable potential due to their distinct modes of action, which encompass DNA interaction, the induction of oxidative stress, and enzyme inhibition, leading to cancerous cell death. Several key challenges hinder the clinical translation of their delivery through nanostructured systems. The drawbacks include poor drug loading, instability during circulation, premature release of drugs, and the risk of toxicity affecting unintended targets and sometimes shows inefficiency in cancer cells.¹²⁴ The heterogeneity and complexity of tumor biology, combined with a lack of understanding about the nano-bio interaction such as the formation of protein corona, immune system recognition, and intracellular trafficking represent further obstacles to the effective use of nano-based therapy of metal complexes.¹²⁵

Researchers are actively developing advanced strategies in order to overcome these limitations, and thereby improve the physicochemical and biological performance of nanocarriers. These strategies encompass optimizing surface chemistry, using biodegradable nanocarriers, creating systems that respond to stimuli, and engineering multifunctional platforms for the co-delivery of drugs and targeting agents.^126,127 Enhancing drug loading efficiency and the stability of nanoparticles continues to be a key priority, as these factors significantly impact the therapeutic index and biodistribution.

Furthermore, many metal-based drugs suffer from poor aqueous solubility, short circulation half-lives, and suboptimal pharmacokinetics. These shortcomings have prompted the development of alternative delivery approaches such as metal-based prodrugs, rational ligand design to improve pharmacological properties, and incorporation into nano-drug delivery systems.¹²⁸ Nanotechnology thus provides a promising avenue for enhancing the therapeutic potential of metal complexes by enabling site-specific delivery to tumor tissues through both passive (EPR effect) and active targeting mechanisms. Additionally, nanocarrier systems offer the ability to modulate drug release kinetics, protect labile metal complexes from degradation, and reduce systemic toxicity. Functionalization of nanocarriers with tumor-specific ligands or antibodies further enhances their accumulation in the tumor microenvironment, potentially lowering the required therapeutic dose and minimizing adverse effects.¹²⁹

Despite these advancements, significant work remains to bridge the gap between preclinical success and clinical implementation.¹³⁰ A deeper understanding of nano-bio interactions, standardized characterization protocols, and robust in vivo validation is essential to improve safety profiles and ensure reproducibility. Essentially, successfully addressing these multifaceted challenges is crucial for taking metal complex-based cancer nanotherapies from the laboratory bench to practical bedside applications, aiming to deliver safer, more effective, and tailored cancer treatments.^131,132

Conclusion and future perspectives

Despite the challenges, nanocarriers have played a major role in enhancing the efficacy of the metal complexes. Recent advances in stimuli-responsive nanocarriers for drug delivery systems (DDSs) show great potential for enhancing cancer therapy. These nanocarriers can respond to both internal stimuli like pH, redox potential, and enzymes, as well as external triggers such as temperature, light, and magnetic fields which can be efficiently utilized for hyperthermia effects and photodynamic properties. This targeted approach allows for controlled drug release at tumor sites, improving efficacy while reducing systemic toxicity. Multi-stimuli responsive systems are particularly promising, offering greater precision in drug delivery, because internal stimuli are complex due to the heterogeneity of human physiological conditions. Additionally, theranostic nanocarriers that combine therapeutic and diagnostic capabilities are gaining attention, enabling real-time monitoring of the treatment response. As research progresses, these advanced DDSs are moving closer to clinical applications, potentially revolutionizing cancer treatment strategies.

Recent advances in nanomedicine have highlighted the potential of various nanocarriers for drug delivery, including polymeric nanoparticles, liposomes, micelles, and dendrimers. These nanocarriers offer improved pharmacokinetics and tumor targeting through the EPR effect. However, challenges such as toxicity, poor biodegradability, and limited clinical translation persist. To address these issues, researchers are exploring hybrid nanoplatforms and surface engineering strategies. Additionally, integrating machine learning and molecular modeling approaches can enhance nanocarrier design and predict their behaviour in biological systems. These interdisciplinary efforts aim to overcome current limitations and improve the clinical translatability of nanomedicines for cancer treatment and other applications.

Recent research highlights the potential of metal-based complexes in cancer therapy, showcasing their ability to interact with DNA and biomolecules, leading to cell death. Nanoparticle-mediated drug delivery systems (NDDSs) have emerged as promising platforms for combining chemotherapy, photodynamic therapy, sonotherapy, and immunotherapy, offering targeted delivery to both cancer and immune cells while reducing toxicity. These nanocarriers can be multifunctionalized to deliver multiple cancer therapeutics, including chemotherapeutics, monoclonal antibodies, and genes, potentially achieving synergistic effects. The integration of metal-based agents with immunotherapy, gene therapy, and other treatment modalities shows promise for developing next-generation combination therapies. However, challenges remain, and continued interdisciplinary research is crucial to overcome current limitations and fully realize the potential of these innovative approaches in cancer treatment.

Cell line abbreviations

MCF-7	Human breast adenocarcinoma cell lines
143B	Human osteosarcoma cancer
Lovo	Human colon adenocarcinoma cell lines
A375	Human malignant melanoma cell lines
HL-7702	Human normal liver cell line
Caki-1	Human clear cell renal cell carcinoma
MDA MB-231	Breast adenocarcinoma cell line
A549	Human alveolar basal epithelial cells
A549cisR	Cisplatin-resistant A549 – drug-resistant variant of A549
HK2	Human kidney proximal tubular epithelial cells
HEK293T	Human embryonic kidney 293 cells
L02	Normal human liver cells
SW620	Human colorectal adenocarcinoma
SW480	Human colorectal adenocarcinoma
HeLa	Human cervical cancer cells
SGC7901	Human gastric cancer cells
HepG2	Human hepatocellular carcinoma
SW620 AD300	Doxorubicin-resistant SW620 variant
4T1	Mouse mammary carcinoma cells
WI-38	Human lung fibroblasts
THP-1	Human monocytic leukemia cells
HaCaT	Immortalized human keratinocytes

Conflicts of interest

There are no conflicts to declare.

Data availability

The data provided in the manuscript are genuine and authentic as per the best of our knowledge.

Acknowledgements

The authors express gratitude to the Department of Science and Technology, Government of India, for support of this research through the DST-SERB CRG project grant (CRG/2021/002267). Additionally, the authors appreciate the Vellore Institute of Technology for facilitating VIT SEED funding. Recognition is also extended to DST, New Delhi, India, for the DST-FIST project.

References

1. F. Bray, M. Laversanne, H. Sung, J. Ferlay, R. L. Siegel, I. Soerjomataram and A. Jemal, Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA Cancer J. Clin., 2024, 74, 229–263.
2. S. Hua, X. Kong, B. Chen, W. Zhuang, Q. Sun, W. Yang, W. Liu and Y. Zhang, Anticancer mechanism of lobaplatin as a monotherapy and in combination with paclitaxel in human gastric cancer, Curr. Mol. Pharmacol., 2018, 11, 316–325.
3. M. R. Gill, J. U. Menon, P. J. Jarman, J. Owen, I. Skaripa-Koukelli, S. Able, J. A. Thomas, R. Carlisle and K. A. Vallis, ¹¹¹In-labelled polymeric nanoparticles incorporating a ruthenium-based radiosensitizer for EGFR-targeted combination therapy in oesophageal cancer cells, Nanoscale, 2018, 10, 10596–10608.
4. J. D. Hoeschele, Dr Barnett Rosenberg – a personal perspective, Dalton Trans., 2016, 45, 12966–12969.
5. T. C. Johnstone, K. Suntharalingam and S. J. Lippard, The next generation of platinum drugs: targeted Pt(II) agents, nanoparticle delivery, and Pt(IV) prodrugs, Chem. Rev., 2016, 116, 3436–3486.
6. S. Alassadi, M. J. Pisani and N. J. Wheate, A chemical perspective on the clinical use of platinum-based anticancer drugs, Dalton Trans., 2022, 51, 10835–10846.
7. S. Rottenberg, C. Disler and P. Perego, The rediscovery of platinum-based cancer therapy, Nat. Rev. Cancer, 2020, 21, 37–50.
8. L. Lucaciu, A. C. Hangan and I. Kostova, Anticancer metallocenes and metal complexes of transition elements from groups 4 to 7, Molecules, 2024, 29, 824.
9. I. Mármol, J. Quero, M. J. Rodríguez-Yoldi and E. Cerrada, Gold as a possible alternative to platinum-based chemotherapy for colon cancer treatment, Cancers, 2019, 11, 780.
10. S. Y. Lee, C. Y. Kim and T. G. Nam, Ruthenium complexes as anticancer agents: a brief history and perspectives, Drug Des., Dev. Ther., 2020, 14, 5375–5392.
11. E. Alessio and L. Messori, NAMI-A and KP1019/1339, Two iconic ruthenium anticancer drug candidates face-to-face: a case story in medicinal inorganic chemistry, Molecules, 2019, 24, 1995.
12. A. D'Amato, A. Mariconda, D. Iacopetta, J. Ceramella, A. Catalano, M. S. Sinicropi and P. Longo, Complexes of ruthenium(II) as promising dual-active agents against cancer and viral infections, Pharmaceuticals, 2023, 16, 1729.
13. C. Sonkar, S. Sarkar and S. Mukhopadhyay, Ruthenium(II)–arene complexes as anti-metastatic agents, and related techniques, RSC Med. Chem., 2022, 13, 22–38.
14. R. Rubbiani, I. Kitanovic, H. Alborzinia, S. Can, A. Kitanovic, L. A. Onambele, M. Stefanopoulou, Y. Geldmacher, W. S. Sheldrick, G. Wolber, A. Prokop, S. Wölfl and I. Ott, Benzimidazol-2-ylidene gold(I) complexes are thioredoxin reductase inhibitors with multiple antitumor properties, J. Med. Chem., 2010, 53, 8608–8618.
15. V. Gandin, A. P. Fernandes, M. P. Rigobello, B. Dani, F. Sorrentino, F. Tisato, M. Björnstedt, A. Bindoli, A. Sturaro, R. Rella and C. Marzano, Cancer cell death induced by phosphine gold(I) compounds targeting thioredoxin reductase, Biochem. Pharmacol., 2010, 79, 90–101.
16. N. Roy and P. Paira, Glutathione depletion and stalwart anticancer activity of metallotherapeutics inducing programmed cell death: opening a new window for cancer therapy, ACS Omega, 2024, 9, 20670–20701.
17. L. Zhou, H. Liu, K. Liu and S. Wei, Gold Compounds and the anticancer immune response, Front. Pharmacol., 2021, 12, 739481.
18. Y. Wang, T. Tang, Y. Yuan, N. Li, X. Wang and J. Guan, Copper and copper complexes in tumor therapy, ChemMedChem, 2024, 19, e202400060.
19. Y. Hu, J. Li, B. Lou, R. Wu, G. Wang, C. Lu, H. Wang, J. Pi and Y. Xu, The role of reactive oxygen species in arsenic toxicity, Biomolecules, 2020, 10, 240.
20. X. Man, S. Li, G. Xu, W. Li, M. Zhu, Z. Zhang, H. Liang and F. Yang, Developing a Copper(II) Isopropyl 2-Pyridyl Ketone Thiosemicarbazone Compound Based On the IB Subdomain of Human Serum Albumin-Indomethacin Complex: Inhibiting Tumor Growth by Remodeling the Tumor Microenvironment, J. Med. Chem., 2024, 67, 5744–5757.
21. M. Jiang, W. Li, J. Liang, M. Pang, S. Li, G. Xu, M. Zhu, H. Liang, Z. Zhang and F. Yang, Developing a Palladium(II) Agent to Overcome Multi-drug Resistance and Metastasis of Liver Tumor by Targeted Multi-acting on Tumor Cell, Inactivating Cancer-associated Fibroblast and Activating Immune Response, J. Med. Chem., 2024, 67, 16296–16310.
22. W. Li, T. Li, Y. Pan, S. Li, G. Xu, Z. Zhang, H. Liang and F. Yang, Designing a mitochondria-targeted theranostic cyclometalated iridium(III) complex: Overcoming cisplatin resistance and inhibiting tumor metastasis through necroptosis and immune response, J. Med. Chem., 2024, 67, 3843–3859.
23. Z. Zhang, J. Zhang, T. Yang, S. Li, G. Xu, H. Liang and F. Yang, Developing an anticancer platinum(II) compound based on the uniqueness of human serum albumin, J. Med. Chem., 2023, 66, 5669–5684.
24. W. J. Li, S. H. Li, X. Y. Man, G. Xu, Z. L. Zhang, Y. Zhang, H. Liang and F. Yang, Designing a novel Au(III) agent to inhibit tumor growth and metastasis through immunogenic cell death induced by combination of endoplasmic reticulum stress and mitochondrial dysfunction, Rare Met., 2025, 44, 430–443.
25. W. Li, S. Li, Z. Zhang, G. Xu, X. Man, F. Yang and H. Liang, Developing a multi-targeted anticancer palladium(II) agent based on the His-242 residue in IIA subdomain of human serum albumin, J. Med. Chem., 2023, 66, 8564–8579.
26. X. Y. Man, M. H. Zhu, S. H. Li, W. J. Li, G. Xu, Z. L. Zhang, X. Y. Wu, H. Liang and F. Yang, Design of a theranostic Gd(III)–Cu(I) complex to inhibit the growth and metastasis of triple-negative breast cancer, Rare Met., 2025, 44, 2589–2604.
27. F. Lu, C. Ouyang, J. Yu, J. González-García, J. Wang, G. Ou, H. Teng, C. Yin and C. Q. Zhou, Smart type I squaraine nano-photosensitizer combined with MnO₂ for tumor-targeted and ferroptosis-induced immunogenic photodynamic therapy, ACS Appl. Mater. Interfaces, 2025, 17, 30637–30652.
28. M. Plaza-Oliver, M. J. Santander-Ortega and M. V. Lozano, Current approaches in lipid-based nanocarriers for oral drug delivery, Drug Delivery Transl. Res., 2021, 11, 471–497.
29. M. Mehta, T. A. Bui, X. Yang, Y. Aksoy, E. M. Goldys and W. Deng, Lipid-based nanoparticles for drug/gene delivery: an overview of the production techniques and difficulties encountered in their industrial development, ACS Mater. Au, 2023, 3, 600–619.
30. M. Stępień, J. Zajda, B. K. Keppler, A. R. Timerbaev and M. Matczuk, Cisplatin meets liposomes for a smarter delivery: A review, Talanta, 2025, 295, 128331.
31. D. Lombardo and M. A. Kiselev, Methods of liposomes preparation: formation and control factors of versatile nanocarriers for biomedical and nanomedicine application, Pharmaceutics, 2022, 14, 543.
32. A. Hafner, J. Lovrić, G. P. Lakǒ and I. Pepić, Nanotherapeutics in the EU: an overview on current state and future directions, Int. J. Nanomed., 2014, 9, 1005–1023.
33. T. Chen, T. Gong, T. Zhao, Y. Fu, Z. Zhang and T. Gong, A comparison study between lycobetaine-loaded nanoemulsion and liposome using nRGD as therapeutic adjuvant for lung cancer therapy, Eur. J. Pharm. Sci., 2018, 111, 293–302.
34. M. Wu, J. Sheng, Q. Xie, Y. Qi, Y. Zhao and S. Zhang, Recent advances in stimuli-responsive hyaluronic acid-based nanodelivery systems for cancer treatment: A review, Int. J. Biol. Macromol., 2025, 144357.
35. A. Akbarzadeh, R. Rezaei-Sadabady, S. Davaran, S. W. Joo, N. Zarghami, Y. Hanifehpour, M. Samiei, M. Kouhi and K. Nejati-Koshki, Liposome: Classification, preparation, and applications, Nanoscale Res. Lett., 2013, 8, 1–9.
36. U. Bulbake, S. Doppalapudi, N. Kommineni and W. Khan, Liposomal formulations in clinical use: An updated review, Pharmaceutics, 2017, 9, 12.
37. N. Tasharrofi, M. Nourozi and A. Marzban, How liposomes pave the way for ocular drug delivery after topical administration, J. Drug Delivery Sci. Technol., 2022, 67, 103045.
38. H. He, Y. Lu, J. Qi, Q. Zhu, Z. Chen and W. Wu, Adapting liposomes for oral drug delivery, Acta Pharm. Sin. B, 2019, 9, 36–48.
39. P. P. Mehta, D. Ghoshal, A. P. Pawar, S. S. Kadam and V. S. Dhapte-Pawar, Recent advances in inhalable liposomes for treatment of pulmonary diseases: Concept to clinical stance, J. Drug Delivery Sci. Technol., 2020, 56, 101509.
40. M. B. R. Pierre and I. Dos Santos Miranda Costa, Liposomal systems as drug delivery vehicles for dermal and transdermal applications, Arch. Dermatol. Res., 2011, 303, 607–621.
41. A. Cevenini, C. Celia, S. Orrù, D. Sarnataro, M. Raia, V. Mollo, M. Locatelli, E. Imperlini, N. Peluso, R. Peltrini, E. De Rosa, A. Parodi, L. Del Vecchio, L. Di Marzio, M. Fresta, P. A. Netti, H. Shen, X. Liu, E. Tasciotti and F. Salvatore, Liposome-embedding silicon microparticle for oxaliplatin delivery in tumor chemotherapy, Pharmaceutics, 2020, 12, 559.
42. D. K. Kirui, C. Celia, R. Molinaro, S. S. Bansal, D. Cosco, M. Fresta, H. Shen and M. Ferrari, Mild hyperthermia enhances transport of liposomal gemcitabine and improves in vivo therapeutic response, Adv. Healthc. Mater., 2015, 4, 1092–1103.
43. M. Jiang, Y. Chu, T. Yang, W. Li, Z. Zhang, H. Sun, H. Liang and F. Yang, Developing a novel indium(III) agent based on liposomes to overcome cisplatin-induced resistance in breast cancer by multitargeting the tumor microenvironment components, J. Med. Chem., 2021, 64, 14587–14602.
44. Y. Opoku-Damoah, Z. P. Xu, H. T. Ta and R. Zhang, Ultrasound-responsive lipid nanoplatform with nitric oxide and carbon monoxide release for cancer sono-gaso-therapy, ACS Appl. Bio Mater., 2024, 7, 7585–7594.
45. C. Sumithaa, T. Manjunathan, O. Mazuryk, S. Peters, R. S. Pillai, M. Brindell, P. Gopinath and M. Ganeshpandian, Nanoencapsulation of Ru(p-cymene) complex bearing ginger-based natural product into liposomal nanoformulation to improve its cellular uptake and antiproliferative activity, ACS Appl. Bio Mater., 2022, 5, 3241–3256.
46. M. Siva, K. Das, S. Guha, S. Sivagnanam, G. Das, A. Saha, A. Stewart, B. Maity and P. Das, Liposomes containing zinc-based chemotherapeutic drug block proliferation and trigger apoptosis in breast cancer cells, ACS Appl. Bio Mater., 2023, 6, 5310–5323.
47. S. Li, Q. Wang, Y. Ren, P. Zhong, P. Bao, S. Guan, X. Qiu and X. Qu, Oxygen and pH responsive theragnostic liposomes for early-stage diagnosis and photothermal therapy of solid tumours, Biomater. Sci., 2023, 12, 748–762.
48. D. Gopalakrishnan, C. Sumithaa, A. M. Kumar, N. S. P. Bhuvanesh, S. Ghorai, P. Das and M. Ganeshpandian, Encapsulation of a Ru(η6-: P-cymene) complex of the antibacterial drug trimethoprim into a polydiacetylene-phospholipid assembly to enhance its in vitro anticancer and antibacterial activities, New J. Chem., 2020, 44, 20047–20059.
49. H. S. Liew, C. W. Mai, M. Zulkefeli, T. Madheswaran, L. V. Kiew, L. J. W. Pua, L. W. Hii, W. M. Lim and M. L. Low, Novel gemcitabine-Re(I) bisquinolinyl complex combinations and formulations with liquid crystalline nanoparticles for pancreatic cancer photodynamic therapy, Front. Pharmacol., 2022, 13, 903210.
50. M. Zhu, S. Xu, G. Li, G. Xu, Z. Zhang, H. Liang and F. Yang, Development of a High Efficacy and Low Toxicity Cobalt(II) Agent for Targeting Inhibition of Tumor Growth Through Mitochondrial Damage-Mediated Chemotherapy and Immunotherapy, J. Med. Chem., 2025, 68, 13113–13126.
51. P. Idlas, E. Lepeltier, G. Bastiat, P. Pigeon, M. J. McGlinchey, N. Lautram, A. Vessières, G. Jaouen and C. Passirani, Physicochemical characterization of ferrocifen lipid nanocapsules: customized drug delivery systems guided by the molecular structure, Langmuir, 2023, 39, 1885–1896.
52. S. A. Gaballa, O. H. El Garhy and H. Abdelkader, Cubosomes: composition, preparation, and drug delivery applications, J. Adv. Biomed. Pharm. Sci., 2020, 3, 1–9.
53. R. Varghese, S. Salvi, P. Sood, B. Kulkarni and D. Kumar, Cubosomes in cancer drug delivery: A review, Colloid Interface Sci. Commun., 2022, 46, 100561.
54. G. E. Giacomazzo, M. Schlich, L. Casula, L. Galantini, A. Del Giudice, G. Pietraperzia, C. Sinico, F. Cencetti, S. Pecchioli, B. Valtancoli, L. Conti, S. Murgia and C. Giorgi, Ruthenium(II) polypyridyl complexes with π-expansive ligands: synthesis and cubosome encapsulation for photodynamic therapy of non-melanoma skin cancer, Inorg. Chem. Front., 2023, 10, 3025–3036.
55. Y. Wang, P. Li, T. T. D. Tran, J. Zhang and L. Kong, Manufacturing techniques and surface engineering of polymer based nanoparticles for targeted drug delivery to cancer, Nanomaterials, 2016, 6, 26.
56. K. Fukushima and Y. Kimura, Stereocomplexed polylactides (Neo-PLA) as high-performance bio-based polymers: Their formation, properties, and application, Polym. Int., 2006, 55, 626–642.
57. M. Sharma, Transdermal and intravenous nano drug delivery systems: present and future, Applications of Targeted Nano Drugs and Delivery Systems: Nanoscience and Nanotechnology in Drug Delivery, 2019, pp. 499–550.
58. Y. Herdiana, N. Wathoni, S. Shamsuddin and M. Muchtaridi, Scale-up polymeric-based nanoparticles drug delivery systems: Development and challenges, OpenNano, 2022, 7, 100048.
59. B. Begines, T. Ortiz, M. Pérez-Aranda, G. Martínez, M. Merinero, F. Argüelles-Arias and A. Alcudia, Polymeric nanoparticles for drug delivery: recent developments and future prospects, Nanomaterials, 2020, 10, 1403.
60. N. Sumit, K. S. Maravajjala, S. Khanna, V. Kachwal, K. L. Swetha, S. Manabala, R. Chowdhury, A. Roy and I. R. Laskar, Rational molecular designing of aggregation-enhanced emission (AEE) active red-emitting iridium(III) complexes: effect of lipophilicity and nanoparticle encapsulation on photodynamic therapy efficacy, ACS Appl. Bio Mater., 2023, 6, 1445–1459.
61. A. Das, B. Bhattacharya, S. Gayen and S. Roy, Suppression of metastasis and angiogenesis by taxifolin ruthenium-p-cymene loaded PLGA nanoparticles in lung carcinoma, Mol. Pharm., 2024, 21, 5496.
62. R. Vinck, A. Gandioso, P. Burckel, B. Saubaméa, K. Cariou and G. Gasser, Red-absorbing Ru(II) polypyridyl complexes with biotin targeting spontaneously assemble into nanoparticles in biological media, Inorg. Chem., 2022, 61, 13576–13585.
63. M. He, R. Wang, P. Wan, H. Wang, Y. Cheng, P. Miao, Z. Wei, X. Leng, Y. Li, J. Du, J. Fan, W. Sun and X. Peng, Biodegradable Ru-containing polycarbonate micelles for photoinduced anticancer multitherapeutic agent delivery and phototherapy enhancement, Biomacromolecules, 2022, 23, 1733–1744.
64. I. Coloma, J. Parrón-Ballesteros, M. Cortijo, C. Cuerva, J. Turnay and S. Herrero, Overcoming resistance of Caco-2 cells to 5-fluorouracil through diruthenium complex encapsulation in PMMA nanoparticles, Inorg. Chem., 2024, 63, 12870–12879.
65. D. Maciel, N. Nunes, F. Santos, Y. Fan, G. Li, M. Shen, H. Tomás, X. Shi and J. Rodrigues, New insights into ruthenium(II) metallodendrimers as anticancer drug nanocarriers: from synthesis to preclinic behaviour, J. Mater. Chem. B, 2022, 10, 8945–8959.
66. N. Pragti, B. K. Kundu, S. Singh, W. A. Carlton Ranjith, S. Sarkar, A. Sonawane and S. Mukhopadhyay, Chitosan-biotin-conjugated pH-responsive Ru(II) glucose nanogel: a dual pathway of targeting cancer cells and self-drug delivery, ACS Appl. Mater. Interfaces, 2023, 15, 43345–43358.
67. L. S. Watson, J. Hughes, S. T. Rafik, A. R. Muguruza, P. M. Girio, S. O. Akponasa, G. Rochford, A. J. MacRobert, N. J. Hodges, E. Yaghini and Z. Pikramenou, Near infra-red luminescent osmium labelled gold nanoparticles for cellular imaging and singlet oxygen generation, Nanoscale, 2024, 16, 16500–16509.
68. X. Wang, J. Wang, J. Wang, Y. Zhong, L. Han, J. Yan, P. Duan, B. Shi and F. Bai, Noncovalent self-assembled smart gold(III) porphyrin nanodrug for synergistic chemo-photothermal therapy, Nano Lett., 2021, 21, 3418–3425.
69. M. Pal, V. Ramu, D. Musib, A. Kunwar, A. Biswas and M. Roy, Iron(III) complex-functionalized gold nanocomposite as a strategic tool for targeted photochemotherapy in red light, Inorg. Chem., 2021, 60, 6283–6297.
70. Z. Jing, X. Sui, J. Yao, J. Xie, L. Jiang, Y. Zhou, H. Pan and W. Han, SKF-96365 activates cytoprotective autophagy to delay apoptosis in colorectal cancer cells through inhibition of the calcium/CaMKIIγ/AKT-mediated pathway, Cancer Lett., 2016, 372, 226–238.
71. Z. Zhang, X. Liu, B. Feng, N. Liu, Q. Wu, Y. Han, Y. Nie, K. Wu, Y. Shi and D. Fan, STIM1, a direct target of microRNA-185, promotes tumor metastasis and is associated with poor prognosis in colorectal cancer, Oncogene, 2015, 34, 4808–4820.
72. J. I. E. Bruce and A. D. James, Targeting the calcium signalling machinery in cancer, Cancers, 2020, 12, 1–34.
73. S. O'Grady and M. P. Morgan, Calcium transport and signalling in breast cancer: Functional and prognostic significance, Semin. Cancer Biol., 2021, 72, 19–26.
74. N. Prevarskaya, R. Skryma and Y. Shuba, Ion channels and the hallmarks of cancer, Trends Mol. Med., 2010, 16, 107–121.
75. J. Shen, X. Liao, W. Wu, T. Feng, J. Karges, M. Lin, H. Luo, Y. Chen and H. Chao, A pH-responsive iridium(III) two-photon photosensitizer loaded CaCO₃ nanoplatform for combined Ca2+ overload and photodynamic therapy, Inorg. Chem. Front., 2022, 9, 4171–4183.
76. J. Karges, D. Díaz-García, S. Prashar, S. Gómez-Ruiz and G. Gasser, Ru(II) polypyridine complex-functionalized mesoporous silica nanoparticles as photosensitizers for cancer targeted photodynamic therapy, ACS Appl. Bio Mater., 2021, 4, 4394–4405.
77. A. M. Ealias and M. P. Saravanakumar, A review on the classification, characterisation, synthesis of nanoparticles and their application, IOP Conf. Ser.: Mater. Sci. Eng., 2017, 263, 032019.
78. A. B. Sengul and E. Asmatulu, Toxicity of metal and metal oxide nanoparticles: a review, Environ. Chem. Lett., 2020, 18, 1659–1683.
79. L. T. Babu, N. Roy, T. Dasgupta, S. Ghosh, R. Tamizhselvi and P. Paira, Toxicity of metal and metal oxide nanoparticles: a review, Chem. Commun., 2024, 60, 13376–13379.
80. Y. Marciano, V. Del Solar, N. Nayeem, D. Dave, J. Son, M. Contel and R. V. Ulijn, Encapsulation of gold-based anticancer agents in protease-degradable peptide nanofilaments enhances their potency, J. Am. Chem. Soc., 2023, 145, 234–246.
81. G. Rabbani and S. N. Ahn, Structure, enzymatic activities, glycation and therapeutic potential of human serum albumin: A natural cargo, Int. J. Biol. Macromol., 2019, 123, 979–990.
82. F. Kratz, A clinical update of using albumin as a drug vehicle—A commentary, J. Controlled Release, 2014, 190, 331–336.
83. G. Fanali, A. Di Masi, V. Trezza, M. Marino, M. Fasano and P. Ascenzi, Human serum albumin: From bench to bedside, Mol. Aspects Med., 2012, 33, 209–290.
84. Z. Liu and X. Chen, Simple bioconjugate chemistry serves great clinical advances: albumin as a versatile platform for diagnosis and precision therapy, Chem. Soc. Rev., 2016, 45, 1432–1456.
85. G. Rabbani, E. J. Lee, K. Ahmad, M. H. Baig and I. Choi, Binding of tolperisone hydrochloride with human serum albumin: effects on the conformation, thermodynamics, and activity of HSA, Mol. Pharm., 2018, 15, 1445–1456.
86. M. Jiang, Z. Zhang, W. Li, X. Man, H. Sun, H. Liang and F. Yang, Developing a copper(II) agent based on His-146 and His-242 residues of human serum albumin nanoparticles: integration to overcome cisplatin resistance and inhibit the metastasis of nonsmall cell lung cancer, J. Med. Chem., 2022, 65, 9447–9458.
87. S. Xu, W. Luo, M. Zhu, L. Zhao, L. Gao, H. Liang, Z. Zhang and F. Yang, Human serum albumin-platinum(II) agent nanoparticles inhibit tumor growth through multimodal action against the tumor microenvironment, Mol. Pharm., 2024, 21, 346–357.
88. Z. Zhang, T. Yang, J. Zhang, W. Li, S. Li, H. Sun, H. Liang and F. Yang, Developing a novel indium(III) agent based on human serum albumin nanoparticles: integrating bioimaging and therapy, J. Med. Chem., 2022, 65, 5392–5406.
89. X. Y. Man, Z. W. Sun, S. H. Li, G. Xu, W. J. Li, Z. L. Zhang, H. Liang and F. Yang, Development of a platinum(II) compound based on indocyanine green@human serum albumin nanoparticles: integrating phototherapy, chemotherapy, and immunotherapy to overcome tumor cisplatin resistance, Rare Met., 2024, 43, 6006–6022.
90. M. Liang, K. Fan, M. Zhou, D. Duan, J. Zheng, D. Yang, J. Feng and X. Yan, H-ferritin-nanocaged doxorubicin nanoparticles specifically target and kill tumors with a single-dose injection, Proc. Natl. Acad. Sci. U. S. A., 2014, 111, 14900–14905.
91. V. V. Sudarev, S. M. Dolotova, S. M. Bukhalovich, S. V. Bazhenov, Y. L. Ryzhykau, V. N. Uversky, N. A. Bondarev, S. D. Osipov, A. E. Mikhailov, D. D. Kuklina, T. N. Murugova, I. V. Manukhov, A. V. Rogachev, V. I. Gordeliy, I. Y. Gushchin, A. I. Kuklin and A. V. Vlasov, Ferritin self-assembly, structure, function, and biotechnological applications, Int. J. Biol. Macromol., 2023, 224, 319–343.
92. M. T. Klem, J. Mosolf, M. Young and T. Douglas, Photochemical mineralization of europium, titanium, and iron oxyhydroxide nanoparticles in the ferritin protein cage, Inorg. Chem., 2008, 47, 2237–2239.
93. P. Santambrogio, S. Levi, P. Arosio, L. Palagi, G. Vecchio, D. M. Lawson, S. J. Yewdall, P. J. Artymiuk, P. M. Harrison, R. Jappelli and G. Cesareni, Evidence that a salt bridge in the light chain contributes to the physical stability difference between heavy and light human ferritins, J. Biol. Chem., 1992, 267, 14077–14083.
94. S. Kang, L. M. Oltrogge, C. C. Broomell, L. O. Liepold, P. E. Prevelige, M. Young and T. Douglas, Controlled assembly of bifunctional chimeric protein cages and composition analysis using noncovalent mass spectrometry, J. Am. Chem. Soc., 2008, 130, 16527–16529.
95. M. Uchida, S. Kang, C. Reichhardt, K. Harlen and T. Douglas, The ferritin superfamily: Supramolecular templates for materials synthesis, Biochim. Biophys. Acta, Gen. Subj., 2010, 1800, 834–845.
96. B. Jiang, X. Jia, T. Ji, M. Zhou, J. He, K. Wang, J. Tian, X. Yan and K. Fan, Ferritin nanocages for early theranostics of tumors via inflammation-enhanced active targeting, Sci. China: Life Sci., 2022, 65, 328–340.
97. Y. Cai, C. Cao, X. He, C. Yang, L. Tian, R. Zhu and Y. Pan, Enhanced magnetic resonance imaging and staining of cancer cells using ferrimagnetic H-ferritin nanoparticles with increasing core size, Int. J. Nanomed., 2015, 10, 2619–2634.
98. K. Fan, C. Cao, Y. Pan, D. Lu, D. Yang, J. Feng, L. Song, M. Liang and X. Yan, Magnetoferritin nanoparticles for targeting and visualizing tumour tissues, Nat. Nanotechnol., 2012, 7, 459–464.
99. K. Fan, X. Jia, M. Zhou, K. Wang, J. Conde, J. He, J. Tian and X. Yan, Ferritin nanocarrier traverses the blood brain barrier and kills glioma, ACS Nano, 2018, 12, 4105–4115.
100. L. Li, C. J. Fang, J. C. Ryan, E. C. Niemi, J. A. Lebrón, P. J. Björkman, H. Arase, F. M. Torti, S. V. Torti, M. C. Nakamura and W. E. Seaman, Binding and uptake of H-ferritin are mediated by human transferrin receptor-1, Proc. Natl. Acad. Sci. U. S. A., 2010, 107, 3505–3510.
101. Y. Tang, Q. Zhang, H. Chen, G. Chen, Z. Li, G. Chen, L. Lin, Z. Yu, M. Su and B. Zhang, A integrated molecule based on ferritin nanoplatforms for inducing tumor ferroptosis with the synergistic photo/chemodynamic treatment, ACS Appl. Mater. Interfaces, 2025, 17, 5909–5920.
102. S. Ghosh, S. Mohapatra, A. Thomas, D. Bhunia, A. Saha, G. Das, B. Jana and S. Ghosh, Apoferritin nanocage delivers combination of microtubule and nucleus targeting anticancer drugs, ACS Appl. Mater. Interfaces, 2016, 8, 30824–30832.
103. X. Li, Y. Zhang, H. Chen, J. Sun and F. Feng, Protein nanocages for delivery and release of luminescent ruthenium(II) polypyridyl complexes, ACS Appl. Mater. Interfaces, 2016, 8, 22756–22761.
104. Z. Yang, X. Wang, H. Diao, J. Zhang, H. Li, H. Sun and Z. Guo, Encapsulation of platinum anticancer drugs by apoferritin, Chem. Commun., 2007, 3453–3455.
105. K. Xiong, Y. Zhou, J. Karges, K. Du, J. Shen, M. Lin, F. Wei, J. Kou, Y. Chen, L. Ji and H. Chao, Autophagy-dependent apoptosis induced by apoferritin-Cu(II) nanoparticles in multidrug-resistant colon cancer cells, ACS Appl. Mater. Interfaces, 2021, 13, 38959–38968.
106. X. Man, W. Li, M. Zhu, S. Li, G. Xu, Z. Zhang, H. Liang and F. Yang, Anticancer Tetranuclear Copper(I) Complex Catalyzes a Click Reaction to Synthesize a Chemotherapeutic Agent In Situ and Achieve Targeted Dual-agent Multi-modal Combination Therapy for Cancer, Angew. Chem., Int. Ed., 2024, 63, e202411846.
107. G. Xu, Q. Liang, L. Gao, S. Xu, W. Luo, Q. Wu, J. Li, Z. Zhang, H. Liang and F. Yang, Developing an Arene Bi-nuclear Ruthenium(II) Complex to Induce Ferroptosis and Activate the cGAS-STING Pathway: Targeted Inhibiting Growth and Metastasis of Triple Negative Breast Cancer, J. Med. Chem., 2024, 67, 19573–19585.
108. W. Li, S. Li, M. Zhu, G. Xu, X. Man, Z. Zhang, H. Liang and F. Yang, Developing a Rhodium(III) Complex to Reprogram Tumor Immune and Metabolic Microenvironment: Overcoming Multidrug Resistance and Metastasis of Non-Small Cell Lung Cancer, J. Med. Chem., 2024, 67, 17243–17258.
109. X. Man, W. Li, M. Zhu, S. Li, G. Xu, Z. Zhang, H. Liang and F. Yang, Rational Design of a Hetero-multinuclear Gadolinium(III)-copper(II) Complex: Integrating Magnetic Resonance Imaging, Photoacoustic Imaging, Mild Photothermal Therapy, Chemotherapy and Immunotherapy of Tumor, J. Med. Chem., 2024, 67, 15606–15619.
110. X. Man, T. Yang, W. Li, S. Li, G. Xu, Z. Zhang, H. Liang and F. Yang, Developing a Gadolinium(III) Compound Based on Apoferritin for Targeted Magnetic Resonance Imaging and Dual-modal Therapy of Cancer, J. Med. Chem., 2023, 66, 7268–7279.
111. B. Wang, Y. P. Timilsena, E. Blanch and B. Adhikari, Lactoferrin: Structure, function, denaturation and digestion, Crit. Rev. Food Sci. Nutr., 2019, 59, 580–596.
112. F. Superti, Lactoferrin from Bovine Milk: A Protective Companion for Life, Nutrients, 2020, 12, 2562.
113. A. Cutone, L. Rosa, G. Ianiro, M. S. Lepanto, M. C. B. Di Patti, P. Valenti and G. Musci, Lactoferrin's Anti-Cancer Properties: Safety, Selectivity, and Wide Range of Action, Biomolecules, 2020, 10, 456.
114. S. Sabra and M. M. Agwa, Lactoferrin, a unique molecule with diverse therapeutical and nanotechnological applications, Int. J. Biol. Macromol., 2020, 164, 1046–1060.
115. M. Arias, A. L. Hilchie, E. F. Haney, J. G. M. Bolscher, M. E. Hyndman, R. E. W. Hancock and H. J. Vogel, Anticancer activities of bovine and human lactoferricin-derived peptides1, Biochem. Cell Biol., 2017, 95, 91–98.
116. A. O. Elzoghby, M. A. Abdelmoneem, I. A. Hassanin, M. M. Abd Elwakil, M. A. Elnaggar, S. Mokhtar, J. Y. Fang and K. A. Elkhodairy, Lactoferrin, a multi-functional glycoprotein: Active therapeutic, drug nanocarrier & targeting ligand, Biomaterials, 2020, 263, 120355.
117. T. Yang, Z. Zhang, J. Zhang, Y. Li, W. Li, H. Liang and F. Yang, Developing a Gallium(III) Agent Based on the Properties of the Tumor Microenvironment and Lactoferrin: Achieving Two-Agent Co-delivery and Multi-targeted Combination Therapy of Cancer, J. Med. Chem., 2023, 66, 793–803.
118. X. Zhang, Q. Zong, T. Lin, I. Ullah, M. Jiang, S. Chen, W. Tang, Y. Guo, Y. Yuan and J. Du, Self-assembled metal-phenolic network nanoparticles for delivery of a cisplatin prodrug for synergistic chemo-immunotherapy, Biomater. Sci., 2024, 12, 3649–3658.
119. A. Nsubuga, N. Fayad, F. Pini, M. M. Natile and N. Hildebrandt, Small upconversion-ruthenium nanohybrids for cancer theranostics, Nanoscale, 2025, 17, 3809–3821.
120. B. K. Kundu, Pragti, W. A. Carlton Ranjith, U. Shankar, R. R. Kannan, S. M. Mobin, A. Bandyopadhyay and S. Mukhopadhyay, Cancer-targeted chitosan-biotin-conjugated mesoporous silica nanoparticles as carriers of zinc complexes to achieve enhanced chemotherapy in vitro and in vivo, ACS Appl. Bio Mater., 2021, 5, 190–204.
121. W. Ishaniya, C. Sumithaa, M. Subramani, A. Karanath-Anilkumar, G. Munuswamy-Ramanujam, A. Madan Kumar, S. Rajendran and M. Ganeshpandian, Polydiacetylene/lipid-coated red-emissive silica nanorods for the sustained release and ameliorated anticancer efficacy of a Ru(arene) complex bearing piperlongumine natural product, Dalton Trans., 2024, 53, 1616–1629.
122. Z. Wang, L. Li, W. Wang, R. Wang, G. Li, H. Bian, D. Zhu and M. R. Bryce, Self-assembled nanoparticles based on cationic mono-/AIE tetra-nuclear Ir(iii) complexes: long wavelength absorption/near-infrared emission photosensitizers for photodynamic therapy, Dalton Trans., 2023, 52, 1595–1601.
123. L. Wei, X. He, C. Liu, M. Kandawa-Shultz, G. Shao and Y. Wang, Biotin-functionalized iridium-based nanoparticles as tumor targeted photosensitizers for enhanced oxidative damage in tumor photodynamic therapy, ACS Appl. Nano Mater., 2024, 7, 1170–1180.
124. K. Elumalai, S. Srinivasan and A. Shanmugam, Review of the efficacy of nanoparticle-based drug delivery systems for cancer treatment, Biomed. Technol., 2024, 5, 109–122.
125. H. Shi, T. Fang, Y. Tian, H. Huang and Y. Liu, A dual-fluorescent nano-carrier for delivering photoactive ruthenium polypyridyl complexes, J. Mater. Chem. B, 2016, 4, 4746–4753.
126. A. L. Lainé and C. Passirani, Novel metal-based anticancer drugs: a new challenge in drug delivery, Curr. Opin. Pharmacol., 2012, 12, 420–426.
127. K. Saravanakumar, X. Hu, D. M. Ali and M.-H. Wang, Emerging strategies in stimuli-responsive nanocarriers as the drug delivery system for enhanced cancer therapy, Curr. Pharm. Des., 2019, 25, 2609–2625.
128. C. Ding, L. Tong, J. Feng and J. Fu, Recent advances in stimuli-responsive release function drug delivery systems for tumor treatment, Molecules, 2016, 21, 1715.
129. S. Roszkowski and Z. Durczynska, Advantages and limitations of nanostructures for biomedical applications, Adv. Clin. Exp. Med., 2025, 34, 447–456.
130. X. J. Gao, K. Ciura, Y. Ma, A. Mikolajczyk, K. Jagiello, Y. Wan, Y. Gao, J. Zheng, S. Zhong, T. Puzyn and X. Gao, Toward the integration of machine learning and molecular modeling for designing drug delivery nanocarriers, Adv. Mater., 2024, 36, 2407793.
131. J. J. Wilson and T. C. Johnstone, The role of metals in the next generation of anticancer therapeutics, Curr. Opin. Chem. Biol., 2023, 76, 102363.
132. S. Abdolmaleki, A. Aliabadi and S. Khaksar, Riding the metal wave: A review of the latest developments in metal-based anticancer agents, Coord. Chem. Rev., 2024, 501, 215579.

---