Engineering silica nanoparticles for precision nanomedicine: synthesis & functionalization – a review

Abstract

Silica nanoparticles are extensively utilized in the biomedical field due to their large surface area, biocompatibility, chemical stability, and tunable surface properties. Their surface can be conveniently modified to support a wide array of applications such as targeted drug delivery, biosensing, and cellular imaging. The silica surface offers abundant reactive sites, enabling straightforward functionalization with a variety of chemical groups to impart specific properties or enhance performance for desired applications. This review presents a detailed account of different synthesis approaches for silica nanoparticles along with methods for introducing various functional groups onto their surfaces. Special emphasis is placed on functionalization techniques tailored for applications in drug delivery, cancer treatment, bioimaging, and biosensing. Furthermore, the review provides a critical evaluation of nanosilica toxicity to ensure their safe deployment in nanomedicine. By critically evaluating current progress and limitations, this review aims to support the development of next-generation silica-based nanocarriers for efficient and safe drug delivery systems.

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Sustainability spotlight

Engineering silica nanoparticles for precision nanomedicine represents a sustainable convergence of materials science and healthcare innovation. By enabling the synthesis and functionalization of biocompatible, abundant, and cost-effective silica, this approach reduces dependence on scarce or toxic nanomaterials while minimizing environmental footprints. Harnessing green synthesis routes and waste-derived silica sources, such as agricultural residues, further advances circular economy principles, transforming low-value byproducts into high-value medical nanomaterials. In doing so, silica nanomedicine not only offers precise, targeted drug delivery and diagnostic solutions but also exemplifies how sustainable material engineering can align advanced healthcare with ecological responsibility.

1 Introduction

Nanotechnology is the interdisciplinary field dedicated to understanding the design, synthesis, and manipulation of matter at the nanoscale. Various nanodevices, such as carbon nanotubes, quantum dots, and polymeric micelles, have been extensively explored in the realm of nanotechnology. They have recently emerged as highly promising materials for drug delivery in nanomedicine, offering advantages such as improved encapsulation, enhanced bioavailability, controlled release, and reduced toxicity.¹ Nanoparticles, including liposomes, polymeric nanoparticles, and metallic nanoparticles, provide multiple benefits compared to conventional drug delivery approaches.² Their higher encapsulation efficiency towards both hydrophilic and hydrophobic drugs protects them from degradation and enhances their stability. Encapsulation enhances the bioavailability of drugs with poor solubility and enables targeted transport to specific cells or tissues, minimizing off-target effects while improving therapeutic effectiveness.^3,4 Controlled release is another significant advantage of nanoparticle-based drug delivery. These systems can be engineered to release drugs at a controlled rate over an extended period, maintaining therapeutic drug levels within the desired range. Furthermore, nanoparticle-based drug delivery systems can be designed to respond to specific biological cues, such as pH or redox conditions, to release drugs at the desired site of action.⁵

Precision nanomedicine refers to the tailoring of therapeutic and diagnostic interventions to the individual characteristics of each patient – such as molecular, cellular or microenvironmental heterogeneity – using nanoscale delivery systems. Traditionally, nanoparticle-based therapies have often applied a “one-size-fits-all” approach. However, in the precision era, the goal is to engineer nanoparticles that can navigate the specific biological barriers, target the relevant cell types, and adapt to the patient's unique disease biology. For instance, the review by Mitchell et al. describes how nanoparticles are being designed to overcome heterogeneous systemic, microenvironmental and cellular-barriers to delivery, thereby enabling a more personalized approach.⁶ Thus, precision nanomedicine merges the fields of nanotechnology, drug delivery and personalized medicine to refine efficacy, reduce off-target effects, and account for patient-to-patient variability. Recent advances in nanoparticle technology that support precision nanomedicine include polymeric nanocarriers and functionalized materials, inorganic nanoparticles, “smart” nanoparticle systems, etc. For example, recent work on functional polyaspartamide-based polymers has shown their promise as biocompatible, tunable nanocarriers for biomedical applications (drug delivery and imaging) thanks to their degradability and functionalization potential.⁷ A recent review focusing on silica-based nanoparticles highlights how detailed investigation into nano-bio interactions is critical for the successful translation of nanoparticle systems.⁸ Nanoparticles are increasingly being built to respond to specific cues (e.g., tumor microenvironment pH, enzyme overexpression, and redox state) enabling triggered release and improved specificity – a clear advantage in precision therapy.⁶ Thus, precision nanomedicine leverages the ability of nanoparticles to deliver therapeutic and diagnostic cargoes in a targeted and patient-specific manner.

Silica and silicon-based nanomaterials are utilized across a wide range of fields, including drug and gene delivery, regenerative medicine, tissue engineering, lightweight aggregates, cancer diagnosis and treatment, catalytic processes, and energy storage.⁹ Among them, silica nanoparticles, especially mesoporous silica nanoparticles (MSNs) first reported in 1992 by the Mobil Oil Corporation, have attracted considerable interest because of their distinctive chemical and structural features.¹⁰ MSNs exhibit a large surface area, adjustable pore sizes, low toxicity, and excellent drug-loading potential, all of which support effective encapsulation and controlled release of therapeutic agents.¹¹ Structurally, the MSNs possess a honeycomb-like framework with an active surface that can be easily functionalized, allowing the modification of surface properties and the attachment of drugs or biomolecules. Different pore geometries of the MSNs are illustrated in Fig. 1.

Fig. 1 Various pore geometries of mesoporous structures of silica nanoparticles.

Their mesoporous structure provides the encapsulation of a variety of therapeutic agents like small molecules, proteins, and nucleic acids, enhancing their stability and bioavailability.¹² In 2012, Caruso and team developed a novel method by utilizing mesoporous silica particles as templates to fabricate submicrometer-sized polymer capsules intended for anticancer drug delivery.¹³ A list of various drug delivery methods for silica nanoparticles and their specific applications is summarized in Table 1.

Table 1 Drug delivery methods for silica nanoparticles and their applications

Type of silica nanoparticle system	Drug delivery method	Applications	References
Bare MSNs	Physical encapsulation and adsorption	Anticancer drug delivery	14
Surface-functionalized MSNs	Stimuli-responsive release (pH, redox, and enzyme)	Targeted cancer therapy and intracellular release	15
Polymer-coated MSNs	Controlled/sustained drug release	Oral delivery, improved stability in the GI tract	16
Targeted MSNs (e.g., folate and antibody)	Ligand-mediated receptor targeting	Tumor-specific delivery, e.g., breast or liver cancer	17
Biodegradable MSNs	Gradual release and breakdown	Safer delivery in chronic treatments	18
Hollow silica nanoparticles (HSNs)	Drug encapsulation in hollow core	Large molecule/protein delivery, chemo drugs	19

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The synthesis of MSNs typically involves sol–gel processes and surfactant-templated approaches, which allow fine control over particle morphology, pore structure, and surface chemistry. These nanoparticles can be easily functionalized with targeting ligands, responsive moieties, or polymeric coatings to achieve site-specific and stimuli-triggered drug release, making them highly suitable for treating complex diseases such as cancer, infections, and inflammatory disorders.

Furthermore, MSNs demonstrate good biocompatibility and biodegradability, and their surfaces can be tailored to enhance cellular uptake and reduce immunogenicity. The versatility of mesoporous silica in encapsulating hydrophilic, hydrophobic and even bio macromolecules positions them at the forefront of nano-medicine research. This review explores the significance of mesoporous silica nanoparticles in precision nanomedicine applications (i.e. drug delivery), detailing their synthesis, surface engineering, advantages and disadvantages over conventional drug carriers.

2 Feedstocks for silica nanoparticle synthesis

Silica nanoparticles are commonly synthesized using both conventional chemical precursors and natural or waste-derived materials. The choice of feedstock plays a critical role in determining the properties, cost and environmental impact of the nanoparticles produced. Tetraethyl orthosilicate (TEOS) and tetramethyl orthosilicate (TMOS) are widely used silica precursors in the sol–gel and Stöber methods. These are silicon alkoxides that undergo hydrolysis and condensation reactions in the presence of a catalyst (acid or base) to form colloidal silica nanoparticles with controlled growth of monodisperse silica spheres in the micron size range.²⁰ To promote sustainability as well as to reduce costs, researchers have recycled agricultural waste as a renewable resource of silica due to their high silica content.^21–23Table 2 summarizes the synthesis of various silica particles by using different feedstocks and methods.

Table 2 Some examples of synthesized silica particles from different feedstocks

Feedstocks	Synthesis methods	Products	Size	References
Rice husk	Acid treatment	Amorphous silica	0.50–0.70 µm	24
Coconut husk	Acid treatment	Crystalline silica	200–750 nm	25
Fly ash	Acid leaching followed by NaOH treatment	Amorphous silica	2.8 nm	26
Rice husk	Open burning followed with acid treatment	Amorphous silica	NA	27
Coconut husk	NaOH treatment	Amorphous silica	NA	28
Rice husk	NaOH treatment	Amorphous silica	<200 nm	29
Palm kernel cell	Sol–gel method	Amorphous silica	50–98 nm	30
Wheat straw	Acid treatment and calcination	Silica particles	100–120 nm	31
Banana leaves	Precipitation method	Silica powder	1–2 µm	32
Sugarcane bagasse	Surfactant mediated synthesis	Amorphous silica	20 nm	33
Olive stones	Alkali leaching treatment	Amorphous silica	15–68 nm	34
Corncob husk	Biogenic synthesis using Fusarium culmorum	Silica nanoparticles	40–70 nm	35

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3 Synthesis methods of silica nanoparticles

The synthesis method plays a very important role in controlling nanoparticle properties like structure, size and morphology.^8,9 As shown in Fig. 2, the various techniques for synthesizing silica particles are classified into two main groups: top-down and bottom-up approaches. The methods for preparing silica nanoparticles can be further categorized into physical methods, chemical methods, and green synthesis techniques.

Fig. 2 Classification of synthesis methods for silica nanoparticles.

3.1. Physical methods

The synthesis of silica nanoparticles using physical methods involves the application of external forces like heat or mechanical energy to promote particle formation. Examples of these methods include evaporation condensation method, physical pulverization, mechanical ball milling, and ion sputtering method.

3.1.1 Evaporation condensation method. This method has wide applications, involves heating a silica source until it evaporates, and followed by cooling the vapor to condense it back into fine silica particles. This process allows the formation of nanoparticles through the transition between the gaseous and solid phases. The method is relatively straightforward; however, it suffers from low yield and requires sophisticated equipment. Additionally, the collection of silica nanoparticles during the operational process is complex and presents significant challenges.^36,37

3.1.2 Physical pulverization. This involves the mechanical breakdown of bulk silica particles into nanoparticles through processes like grinding and milling. This technique relies on applying outside tension to reduce the particle size but often requires prolonged processing times and can result in a broad particle size distribution.³⁸

3.1.3 Mechanical ball milling. This process involves grinding samples using high energy collision with balls in a rotating mill. This method requires a lot of time and can result in uneven particle sizes and potential contamination from balling media.³⁹

3.1.4 Ion sputtering. In this technique, an inert gas typically argon is introduced in a vacuum chamber. The energetic ion collisions cause atoms or clusters to be ejected from the target surface, which then condense to form nanoparticles.⁴⁰ This technique allows for precise control over particle composition and size. However, it requires complex and expensive equipment, and the overall yield of nanoparticles is relatively low, making it more suitable for specialized applications rather than large scale production.

3.2. Chemical methods

3.2.1 Sol–gel method. To synthesize mesoporous silica nanoparticles (MSNs) with controlled size and enhanced properties using the sol–gel method, a carefully modified procedure is employed, often based on the Stöber process. Stöber was the pioneer in developing a system of chemical reactions for the synthesis of spherical monodisperse micro size silica particles. This is a well-established sol–gel method used to produce uniform and monodisperse silica nanoparticles.^41,42 The synthesis begins with the preparation of a surfactant solution, typically using cetyltrimethylammonium bromide (CTAB), which serves as a structure-directing agent to form the mesoporous framework.⁴³ This solution is stirred and mildly heated to ensure complete dissolution. The pH of the solution is then adjusted using a catalyst commonly ammonia for basic conditions or hydrochloric acid for acidic ones which significantly affects the rates of hydrolysis and condensation of the silica precursor. TEOS is introduced slowly into the surfactant solution under vigorous stirring, initiating hydrolysis and subsequent condensation to form silica networks around the CTAB micelles.⁴⁴ The reaction mixture is allowed to age for several hours, during which particle growth and pore formation occur. The resulting MSNs are then collected by centrifugation, thoroughly washed with ethanol and water, and dried. To remove the surfactant template and create accessible pores, the particles undergo either calcination at high temperatures or solvent extraction using acidic ethanol.⁴⁵ Key synthesis parameters such as CTAB and TEOS concentrations, pH level, reaction temperature, stirring rate, and the use of co-solvents or swelling agents are systematically adjusted to control particle size, pore structure, and surface characteristics. The size of the particles can be finely tuned by adjusting the concentration of TEOS, ammonia, water, and ethanol, with higher concentrations of TEOS and ammonia generally leading to larger particles.^41,46 This tailored sol–gel approach allows for the fabrication of MSNs with desirable properties for a wide range of applications, including drug delivery, catalysis, and sensing.⁴⁷

3.2.2 Evaporation-induced self-assembly (EISA). The EISA method is an effective technique for synthesizing MSNs, prized for its ability to produce highly ordered microstructures with precise control over pore organization and particle morphology. In this method, a precursor solution is first prepared by mixing a silica precursor like TEOS, surfactants, and a solvent.⁴⁶ The surfactant molecules spontaneously self-assemble into micelles, which act as templates for the formation of mesoporous silica. As the solvent gradually evaporates, the concentration of the precursor and surfactant increases, driving the self-assembly of the silica and surfactant into a mesoporous network. This process leads to the creation of a highly ordered silica framework around the surfactant micelles. Once the evaporation is complete, the surfactant template is removed through calcination or solvent extraction, leaving behind a mesoporous silica structure with well-defined pore channels.⁴⁸ The advantages of EISA include the ability to control pore size, pore distribution, and the overall structure of the nanoparticles, as well as its scalability, making it suitable for producing large quantities of MSNs. Furthermore, the method allows for the creation of nanoparticles with various shapes, such as spherical or cylindrical, and enables easy functionalization for targeted drug delivery applications. The high surface area and tunable pore sizes of MSNs synthesized via EISA make them ideal for drug loading and controlled release, enhancing their potential for clinical use in drug delivery and other biomedical applications.⁴⁹

3.2.3 Micro emulsion method. The micro emulsion method is a versatile technique used for the synthesis of nanosilica, including MSNs, offering fine control over particle size and uniformity.⁵⁰ This method utilizes a thermodynamically stable mixture of water, oil, and surfactants, forming nanoscale droplets that serve as reaction vessels for the synthesis of silica nanoparticles.⁵¹ In the micro emulsion process, a silica precursor, such as TEOS, is dissolved in the oil phase, while the water phase contains a small amount of water and surfactants, which stabilize the formation of tiny water droplets within the oil.⁵² These water droplets act as nano reactors, where the hydrolysis and condensation of TEOS occur, leading to the formation of silica. The size of the resulting silica nanoparticles is primarily controlled by the size of the water droplets in the micro emulsion, which can be fine-tuned by adjusting the surfactant concentration, the water-to-oil ratio, and the type of surfactant used.⁵³ One of the key benefits of the micro emulsion method is its ability to produce uniform, monodisperse silica nanoparticles with a narrow size distribution, typically ranging from 10 to 100 nm. This precise control over particle size is especially beneficial for drug delivery applications, where uniformity in size and surface properties can significantly impact the loading capacity, release profile, and biodistribution of the nanoparticles.⁵ Additionally, the micro emulsion method can be used to synthesize nanoparticles with a variety of surface modifications, such as functional groups that enhance drug loading or enable targeted delivery.

The main advantages of the micro emulsion method include its simplicity, the ability to produce small and uniform nanoparticles, and its scalability for producing large quantities of nano silica particles.⁵² However, challenges such as controlling the exact pore structure and achieving high drug loading capacities may require further modifications and post-synthesis treatments. Despite these challenges, the micro emulsion method remains a promising approach for the synthesis of nanosilica and MSNs for various biomedical applications, particularly in the field of drug delivery, due to its versatility and control over particle characteristics.

3.2.4 Soft and hard templating. Soft and hard templating are two methods used to synthesize MSNs, each offering control over their structure and properties. Soft templating uses surfactants or block copolymers, which self-assemble into micelles that direct the formation of mesoporous silica when combined with a silica precursor like TEOS.⁵⁴ After synthesis, the surfactants are removed, leaving behind a well-ordered mesoporous structure. This method provides excellent control over pore size and surface area, making it ideal for drug delivery applications. Hard templating, or nano casting, involves using preformed solid templates, such as polymer beads or carbon particles, around which silica is deposited. After the silica condenses, the template is removed, leaving a mesoporous silica structure with a similar shape to the original template.⁵⁵ This method allows for more complex shapes but is typically more complicated and less scalable than soft templating. Both methods offer advantages depending on the desired particle shape, pore structure, and application, with soft templating excelling in uniformity and hard templating providing flexibility for creating intricate structures.

3.2.5 Electrolysis method. The electrolysis method typically involves two approaches: aqueous solution electrolysis and molten salt electrolysis. It uses direct current to drive non-spontaneous chemical reactions, enabling the separation of elements from natural materials like ores. This technique is capable of producing high-purity ultrafine metal particles, including those that are difficult or impossible to obtain using conventional preparation methods.⁵⁶

3.2.6 Chemical vapor deposition method. This method involves producing silica nanoparticles through chemical reactions occurring on a substrate under heated conditions. It is commonly used for silica nanoparticle synthesis due to its theoretically straightforward operation, ease of product recovery, and the ability to achieve a narrow particle size distribution.⁵⁷

3.2.7 Precipitation method. In aqueous solutions, precipitation involves transforming dissolved raw materials from a supersaturated solution into insoluble solids, known as precipitates. Silica nanoparticles are then obtained through subsequent post-treatment steps. This method can be categorized into direct precipitation, co-precipitation, and uniform precipitation techniques.⁵⁸

3.2.8 Solvent evaporation method. The solvent evaporation method is a technique used to produce silica nanoparticles by dissolving silica precursors in an organic solvent, which is then emulsified in an aqueous phase containing a surfactant. As the organic solvent gradually evaporates under controlled conditions, silica nanoparticles form through hydrolysis and condensation reactions.⁵⁹ This method is valued for its ability to produce uniform nanoparticles with controllable size and morphology, making it suitable for applications in drug delivery and coatings and as nanocomposites.

3.3. Biological methods (green approaches)

The green synthesis of silica nanoparticles involves eco-friendly and sustainable methods that avoid the use of toxic chemicals and excessive energy. These approaches make use of natural materials like plant extracts, agricultural residues, and microorganisms to produce nanoparticles in an environmentally responsible manner.^{9,22,30,60,61} Additionally, green synthesis provides a cost-efficient alternative to conventional methods by eliminating the need for sophisticated equipment and complicated purification processes. Following are the green synthesis methods for producing silica nanoparticles:

3.3.1 Use of agriculture waste. Agricultural waste, especially rice husk and sugarcane bagasse, is a rich and renewable source of silica. Numerous studies in the literature have reported the use of agricultural materials for the synthesis of high-quality silica nanoparticles.^62–65 For example, Jansomboon et al. were the first to synthesize silica micro- and nanoparticles using rice husk as a precursor.⁶² Similarly, Lu et al. utilized rice straw as a silica source to produce highly pure amorphous silica nano discs.⁶³

Rajotia et al. reported the utilization of rice-husk-derived amorphous silica nanoparticles for the fabrication of bioglasses for antibacterial and wound healing applications.⁶⁴ The primary advantage of using agricultural waste lies in its abundant availability at the end of each harvest season. Consequently, nanoparticle synthesis methods based on agricultural waste are generally more cost-effective than conventional approaches.⁶⁵

3.3.2 Industrial waste. Some industrial waste products have proven to be valuable resources for the synthesis of silica nanoparticles with minimal processing. A notable example is the transformation of fly ash into nanosilica. Fly ash, a by-product of coal-fired power plants, is rich in silica. Yadav et al. reported the successful synthesis of amorphous silica nanoparticles from this waste material.⁶¹

3.3.3 Plant extract-mediated synthesis. This method uses extracts from various plants which contain natural compounds such as flavonoids, polyphenols, and sugars. Numerous studies in the literature have documented the green synthesis of nanoparticles using a wide variety of plant sources. Durairaj et al. synthesized silica nanoparticles using the well-established sol–gel method with ash derived from Bambusa vulgaris leaves and applied them in environmental applications.⁶⁵ Jabeen et al. demonstrated the synthesis of silica nanoparticles utilizing Azadirachta indica (Neem) leaf extract, which functioned as an efficient chelating agent in the process.⁶⁶

3.3.4 Microbial synthesis. Certain bacteria, fungi, and diatoms naturally interact with silica compounds and can be used to synthesize silica nanoparticles biologically. Microorganisms are cultured in the presence of silica precursors. Through metabolic processes, they help in the formation of silica particles either within or outside their cells. This method is highly specific, biodegradable, and suitable for biomedical applications due to its biocompatibility. A comparative study summarizing the benefits and limitations of both chemical and biochemical synthesis routes, including aspects such as eco-friendliness, scalability, cost, particle uniformity, reaction control, and biological compatibility is given in Table 3.

Table 3 Advantages and disadvantages of different methods used for silica nanoparticle synthesis^67–72

Methods	Advantages	Challenges	Typical Applications
Sol–gel method	• Simple and widely studied	• Long processing time	• Anticancer drug delivery, catalysis, sensors, and coatings
	• Enables controlled composition & size	• Requires organic solvents
	• High-purity amorphous silica
	• Allows mesoporous control via surfactants
Evaporation-induced self-assembly	• Highly ordered pore arrangement	• Sensitive to humidity & solvent rate	• Drug delivery, catalysis, adsorption, and optical coatings
	• Tunable pore size and morphology	• Requires template removal
	• Scalable synthesis
Microemulsion method	• Excellent control over particle size	• High surfactant cost	• Drug delivery, imaging, and biosensors
	• Uniform and monodisperse nanoparticles	• Difficult purification
	• Mild synthesis conditions	• Limited control over pore ordering
Soft templating	• High surface area & pore uniformity	• Template removal required	• Drug delivery, adsorption, and catalysis
	• Easy control of pore size	• Sensitive to pH & temperature
	• Suitable for MSN
Hard templating (nanocasting)	• Complex and tunable shapes possible	• Multi-step, costly	• Catalysis, photonics, and advanced composite materials
	• High pore regularity and uniformity	• Difficult to scale-up
		• Template removal may damage structure
Electrolysis method	• Produces high-purity ultrafine particles	• Requires specific equipment	• Metal-silica composites and specialized coatings
	• Suitable for special material synthesis	• Energy intensive
		• Limited uniformity control
CVD	• Produces uniform coatings and nanoparticles	• High temperature needed	• Coatings, optical films, and microelectronics
	• Scalable and clean process	• Expensive precursors & setup
	• Narrow particle size distribution
Hydrothermal method	• Uniform & well-dispersed nanoparticles	• Expensive equipment	• Catalysts, sensors, and bioactive materials
	• High crystallinity & purity	• Long reaction time
	• Controlled morphology	• Limited scalability
Solvent evaporation method	• Produces uniform nanoparticles	• Requires surfactant stabilization	• Drug delivery, coatings, and nanocomposites
	• Tunable morphology	• Control of solvent rate critical
	• Simple operation
Green synthesis with waste	• Renewable, cost-effective & eco-friendly	• Impurities (metal oxides, carbon, etc)	• Adsorbents, bioactive glass, composites, construction, and adsorbents
	• Utilizes waste materials	• Irregular particle size
	• High silica yield

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3.4. Surface functionalization of MSNs

Surface functionalization of silica nanoparticles enables precise control over their surface chemistry, facilitating targeted delivery and improved drug loading. These features make them a promising choice for biomedical applications.^73–75 Through the incorporation of dopants, chemical alteration of surface groups, and diverse assembly strategies, it is possible to design multifunctional nanoparticles that serve both therapeutic and diagnostic roles, such as carrying imaging agents along with drugs or heat-generating elements.^74,76 Several techniques are used for the surface functionalization of silica particles to enhance their properties for specific applications. Common methods include silanization, where organosilanes are grafted onto the surface to introduce functional groups,⁷⁷ co-condensation, which involves incorporating functional groups during the synthesis process, and layer-by-layer assembly for multilayer coatings. Additionally, physical adsorption and polymer grafting are employed to attach biomolecules, drugs, or imaging agents.⁷⁸ These techniques enable precise control over surface chemistry, improving biocompatibility, targeting ability, and loading efficiency in biomedical applications. Table 4 summarizes some important studies based on the surface functionalization of silica nanoparticles.

Table 4 Surface functionalization of silica nanoparticles for different applications

Methods	Substrate materials	Applications	References
Co-condensation and post-grafting	Amino groups	Cancer drug delivery	73 and 79
Polymer coating	poly(2-(diethylamino)ethyl methacrylate)	Drug delivery	75 and 80
Hydrophobic silanization	Alkyltrichlorosilanes	Adsorbent, catalyst, microfluidic	81
Plasma polymer coating	SUS 304 stainless steel, petroleum hydrocarbon removal	Biomedical implant	82 and 83
Doping	Metal and metal oxides (ag, Ni)	Catalyst	84
Surface coating	CdSe@ZnS QDs, γ-Fe2O3	Bio imaging	85
Silanization	3-Glycidoxypropyltrimethoxysilane (GPTS) and amines	Gene transfer	86
Surface coating	Gd[DO3A-hexylamine]	MRI	87 and 88
Silanization	(3-Aminopropyl) triethoxysilane	Drug delivery	89

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From the table, we can observe that the choice of agents for functionalization affects its field application. To enhance the specificity of silica nanoparticles for interacting with target cells, linker molecules are also employed during the bio conjugation process. These linkers connect antibodies to the nanoparticle surface via interactions between functional groups on the silica and specific amino acid residues of the antibody. The primary role of the linker is to introduce spatial separation between the antibody and the nanoparticle surface, thereby reducing the risk of antibody denaturation or steric hindrance that might impair its biological activity. Two main strategies are typically used: monovalent and multivalent linkers.⁹⁰ Monovalent homofunctional linkers, such as glutaraldehyde, facilitate the formation of imine bonds between amine groups on the silica nanoparticle surface and lysine residues on immunoglobulins (IgG). However, this approach can lead to undesirable aggregation. To overcome such limitations, monovalent heterofunctional linkers like sulfosuccinimidyl 4-[N-maleimidomethyl] cyclohexane-1-carboxylate (sulfo-SMCC) are preferred. Sulfo-SMCC enables effective coupling between sulfhydryl groups on the nanoparticle surface and lysine residues on IgG, offering improved stability and reduced aggregation during conjugation.^91,92

3.5. Key challenges

The key challenges in producing high-quality and reproducible silica nanoparticles for biomedical and therapeutic applications are batch-to-batch reproducibility, control over particle size and uniformity, surface modification and functionalization, scalability and process standardization, aggregation and stability, and quality control and characterization.^5,16,93,94 Maintaining consistent particle size, morphology, and surface characteristics remains difficult due to the sensitivity of sol–gel and templating synthesis methods to reaction parameters such as pH, temperature, precursor concentration, and mixing rate.^5,16 Precise control of nanoparticle size and pore structure is crucial for predictable drug loading and release, yet even small variations in synthesis can lead to polydispersity and altered functionality.¹⁶ Achieving stable, uniform, and reproducible surface coatings or targeting ligands without altering nanoparticle stability or aggregation behavior is technically challenging.^5,16,93 Transitioning from laboratory-scale synthesis to industrial production often leads to changes in particle properties and reproducibility issues due to lack of standardized manufacturing protocols.^5,94 Silica nanoparticles are prone to aggregation during synthesis, purification, and storage, affecting their dispersibility, bioavailability, and reproducibility.¹⁶ Reliable analytical techniques are required to ensure reproducibility in structural, chemical, and surface properties across batches – an area still limited by methodological variability.⁵ Thus, reproducible synthesis of high-quality silica nanoparticles is hindered mainly by difficulties in controlling physicochemical parameters, ensuring batch consistency, and scaling up production while maintaining uniformity and stability.

4 Characterization of MSNs

The synthesis of MSNs has evolved through several advanced characterization techniques aimed at improving structural control, scalability, and drug-loading efficiency.^95,96 These methods help to determine various properties including particle size, shape, crystalline, pore size, and surface area. The EISA method allows reactants to undergo concentration changes during solvent evaporation, leading to the formation of liquid crystal-like silica structures. Fontecave et al. later modified this approach by incorporating amphiphilic drugs as both structure-directing agents and active cargos, eliminating the need for toxic surfactants and achieving high drug-loading efficiency with minimized burst release.⁹⁷ A spray dryer operating under adequate airflow and pressure conditions was utilized to transform the precursor droplets into solid mesoporous particles. TEM analysis confirmed that the resulting particles exhibited pore size and structural features comparable to those obtained using cetyltrimethylammonium bromide as the surfactant template.⁹⁸ An alternative mechanism, known as the “swelling-shrinking mechanism”, also has been proposed to explain the formation of MSNs, based on observations made using time-resolved synchrotron small-angle X-ray scattering (SAXS) analysis.⁹⁹ The in situ time-resolved small-angle neutron scattering (SANS) technique has been employed to monitor the real-time formation of MSNs.^100,101 This analysis revealed that during the initial hydrolysis of TMOS, silicate species begin to accumulate around surfactant micelles. As hydrolysis and condensation progress, the surface charge decreases, reducing intermicellar repulsion and promoting the aggregation of silica frameworks. Later, well-defined hexagonally ordered mesopores were observed, as confirmed by TEM, supporting the “current bun model” of MSN formation.^100,101

5 Silica nanoparticles for precision nanomedicine

5.1. Drug delivery

Silica nanoparticles have emerged as versatile platforms for targeted and controlled drug delivery due to their tunable pore size, large surface area, and easy surface functionalization. They enable high drug loading efficiency, protection of therapeutic agents, and stimuli-responsive release, enhancing drug bioavailability and reducing systemic toxicity.^96,102,103 Their surface can be modified with ligands for site-specific delivery, improving therapeutic outcomes in diseases such as cancer and autoimmune disorders.^104,105 Overall, silica nanoparticles represent a promising nanocarrier system for achieving precision and efficacy in modern drug delivery applications, as depicted in Fig. 3.

Fig. 3 Schematic representation of applications of silica nanoparticles in drug delivery.

5.1.1. Targeted drug delivery. Silica nanoparticles can be modified with targeting molecules such as antibodies, peptides, or vitamins.^106,107 These modifications enable the particles to specifically recognize and bind to receptors on diseased cells, such as cancer cells. This selective targeting helps concentrate the drug at the intended site, thereby reducing damage to healthy tissues and improving treatment efficiency.

5.1.2. Controlled and sustained drug release. The porous structure of MSNs makes them excellent carriers for sustained drug release. Drugs can be stored within the nanopores and released slowly over time. Additionally, the release rate can be fine-tuned using external stimuli like pH, temperature, or enzymes, making them ideal for site-specific delivery in environments like tumors or infected tissues.¹⁰⁷ Panja et al. reported the grafting of hyperbranched polyglycerol (HPG) onto silica-coated nanoparticles to enhance their colloidal stability and biocompatibility.¹⁰⁸ The HPG layer provided excellent aqueous dispersibility, resistance to aggregation, and low nonspecific protein adsorption, making the modified nanoparticles ideal for biomedical applications requiring stable and non-fouling nanomaterials.

5.1.3. Combination drug delivery. Silica nanoparticles can carry multiple therapeutic agents simultaneously. This allows the co-delivery of drugs that work together to enhance treatment outcomes or overcome drug resistance.^109,110 For example, in cancer therapy, combining chemotherapy drugs in single nanoparticles can produce a stronger effect than using them separately.¹¹¹ Mesoporous organosilica nanoparticles (MONs) have emerged as promising nanocarriers for the targeted chemotherapy of prostate cancer due to their tunable pore structure, high surface area, and functionalizable organic–inorganic hybrid framework. Das et al. reported the development of antibody-conjugated biodegradable periodic MONs for targeted chemotherapy of prostate cancer.¹¹² Using super-resolution microscopy, they quantified nano periodic mesoporous organosilica (PMO) nanoparticle biodegradation in response to glutathione, as well as the effects of antibody multivalency and orientation on cancer cell targeting.

5.1.4. Cancer immunotherapy. Recent advances in nanotechnology have significantly improved cancer therapy through the development of innovative nanocarrier systems. Theivendran et al.¹¹³ highlighted the potential of mesoporous silica and organosilica nanoparticles as versatile platforms for cancer immunotherapy. Their tunable porosity, large surface area, and modifiable surface chemistry enable efficient antigen delivery, immune activation, and combination with checkpoint inhibitors for enhanced therapeutic efficacy. Complementarily, Cao et al.¹¹⁴ introduced deformable nanocarriers designed to navigate physiological barriers and achieve superior tumor penetration and drug release. These flexible nanocarriers adapt to the complex tumor microenvironment, improving bioavailability and minimizing off-target effects. Together, these studies emphasize that structurally engineered and functionally adaptable nanocarriers represent a promising direction for next-generation, high-precision cancer therapy.

5.1.5. Gene and nucleic acid delivery. With the right surface coatings, silica nanoparticles can also transport genetic material such as DNA, RNA, or mRNA into cells. These particles protect the genetic material from degradation and improve its uptake by target cells, which is beneficial for gene therapy and RNA-based treatments.¹¹⁵

5.1.6. Drug delivery across blood–brain barriers. Some drugs have difficulty reaching certain parts of the body, like the brain. Silica nanoparticles can be designed to cross biological barriers such as the blood–brain barrier.¹¹⁶ This enables the delivery of drugs that would otherwise be ineffective in treating brain-related diseases.

5.1.7. Antimicrobial applications. Silica nanoparticles have shown promise in delivering antibiotics directly to sites of infection. This targeted approach can help reduce bacterial resistance and enhance the effectiveness of antimicrobial treatments, especially in cases of biofilm related infections.^117,118

5.1.8. Gene therapy. Nanoparticles are utilized to deliver genetic material in gene therapy applications, offering the potential to correct genetic disorders by transporting therapeutic genes directly to targeted cells.¹¹⁹

5.2. Impact of silica nanoparticles on hemocompatibility

Hemolysis, defined as the rupture of erythrocyte membranes leading to hemoglobin release or destruction of red blood cells (RBC), serves as a crucial indicator of the hemocompatibility of silica nanoparticles. The extent of hemolytic activity is strongly influenced by multiple physicochemical parameters such as particle size, morphology, surface chemistry, and surface roughness.⁸ Experimental investigations have demonstrated a size and concentration dependent hemolytic response; wherein larger silica nanoparticles generally induce greater erythrocyte membrane disruption due to enhanced interfacial interactions between surface silanol groups and phosphatidylcholine moieties of RBC membranes. Lin et al. had studied the effect of different particle sizes in hemolysis and reported that hemolytic activity is directly proportional to the size of MSNs.¹²⁰ Also, some studies showed that high mass with a small size of silica nanoparticles demonstrated increasing hemolytic activity. In contrast, smaller silica nanoparticles (<50 nm) typically exhibit reduced hemolytic potential owing to their larger surface area-to-volume ratio and improved colloidal stability.¹²¹ Furthermore, particle morphology also plays a critical role, and spherical nanoparticles tend to exhibit superior hemocompatibility compared to their rod-shaped or tubular counterparts. Surface functionalization, including amine modification, PEGylation, or lipid bilayer coating, has been shown to substantially mitigate hemolytic activity by shielding reactive silanol groups and diminishing electrostatic interactions with erythrocyte membranes.^122,123 Additionally, surface roughness modulates MSN-cell membrane interactions, where smoother surfaces such as those in HMS and MSU-type silica nanoparticles enhance hydrothermal stability and reduce membrane perturbation.¹²⁴ Collectively, these findings suggest that hemolytic behavior is governed by a complex interplay between MSN physicochemical characteristics and membrane interaction dynamics, emphasizing the necessity of precise surface engineering to ensure the biocompatibility and safety of MSN-based drug delivery systems. Rajotia et al. developed silica-incorporated bioactive glass composites and evaluated their potential in wound healing applications. The in vivo studies demonstrated that the silica-based bioglass exhibited excellent regenerative and wound healing efficacy, promoting rapid tissue repair and enhanced epithelialization. These findings highlight the crucial role of silica incorporation in improving the bioactivity, biocompatibility, and therapeutic performance of bioglass materials for advanced biomedical applications.⁶⁴

5.3. Safety and biodegradation of silica nanoparticles

The safety and biodegradation of silica nanoparticles are critical factors that influence their suitability for clinical drug delivery applications. Among the most used administration routes for silica nanoparticles are intravenous, subcutaneous, and intratumoral injections. Intravenous administration offers the advantage of rapid systemic distribution via the bloodstream, enabling the nanoparticles to reach target sites throughout the body efficiently.¹²⁵ Their structural integrity ensures that the drug remains shielded from enzymatic degradation, hydrolysis, and other destabilizing factors in the blood.^102,105 Importantly, once the nanoparticles reach their target site and release their therapeutic payload, it is desirable for them to undergo biodegradation into non-toxic by-products that can be safely eliminated from the body, typically through renal or hepatic pathways.^104,106 The degradation of silica nanoparticles generally occurs via hydrolysis of the silica matrix into silicic acid, a biocompatible compound that is naturally excreted.¹²⁶ The degradation rate can be finely tuned by modifying the synthesis parameters, such as pore size, particle size, surface functionalization, and degree of condensation of the silica network. Fig. 4 depicts the interconnection between oxidative stress, autophagy dysfunction, and inflammasome activation leading to inflammatory outcomes. In addition, Rabolli et al. (2010) reported an in vitro study of the effect of size, porosity and surface area on the cytotoxicity of silica nanoparticles.¹²⁷ Dong et al. (2020) reported a detailed study on the size dependent cytotoxicity of silica nanoparticles.¹²⁸

Fig. 4 The mechanism for toxicity of silica particles includes pro-inflammatory response, autophagy and oxidative stress.

Despite notable advancements in silica nanoparticles over other inorganic nanomaterials, investigating their potential toxicity is still crucial. The harmful effects of silica nanoparticles are largely influenced by characteristic size, shape, surface charge, crystalline structure, and concentration. For example, positively charged silica nanoparticles have been found to generate stronger toxic responses through reactive oxygen species (ROS) compared to their negatively or neutrally charged counterparts.¹²⁹ The cytotoxicity of silica nanoparticles toward normal cells can be explained by two main factors: (i) they increase oxidative stress within cells by promoting the generation of harmful ROS and reducing glutathione levels a key molecule involved in maintaining redox balance which in turn causes lipid peroxidation and eventually leads to cell death, and (ii) the free Si–OH groups present on the surface of silica nanoparticles can electrostatically interact with the phospholipids in the cell membrane, resulting in membrane disruption and damage. Considering all these points, we need to give attention to the surface functionalization of silica nanoparticles to decrease their toxicity.

6 Conclusions and perspectives

Silica nanoparticles, particularly mesoporous silica nanoparticles (MSNs), have established themselves as one of the most versatile and promising nanoplatforms for biomedical applications. Their unique combination of large surface area, tunable pore structure, controllable morphology, and ease of surface modification enables efficient drug loading, targeted delivery, and controlled release. The review highlights that diverse synthesis strategies, from conventional sol–gel and micro-emulsion techniques to sustainable green approaches using agricultural or industrial wastes, offer flexibility in tailoring structural and physicochemical properties for specific biomedical purposes. Surface functionalization through silanization, co-condensation, polymer coating, and bio-conjugation further extends their potential, allowing the integration of targeting ligands, responsive moieties, and imaging agents for multifunctional therapeutic systems.

However, despite significant progress, several critical challenges remain before silica nanoparticles can be fully translated into clinical practice. Controlling batch-to-batch reproducibility, ensuring colloidal stability, minimizing aggregation, and achieving scalable manufacturing remain key technical hurdles. Moreover, understanding the complex interactions between MSNs and biological systems, including protein corona formation, immune response, hemocompatibility, and long-term biodistribution, requires deeper investigation. Although silica degradation into biocompatible silicic acid is advantageous, the rate and mechanism of biodegradation must be carefully optimized to balance drug retention and clearance. Addressing toxicity concerns through the rational design of particle size, surface charge, and functionalization is essential to ensure biosafety.

Looking forward, the next generation of silica-based nanomedicines will likely evolve toward precision-engineered, stimuli-responsive, and biodegradable systems capable of delivering therapeutics with spatiotemporal control. Integration of artificial intelligence (AI) and machine learning (ML) tools into nanoparticle design can accelerate optimization by predicting nano–bio interactions and performance outcomes. Furthermore, combining silica nanoparticles with other functional materials such as polymers, lipids, or metals could yield hybrid nanostructures with enhanced diagnostic and therapeutic functionalities. Emphasis should also be placed on developing environmentally sustainable, cost-effective synthesis routes to promote scalability and regulatory acceptance.

In conclusion, silica nanoparticles stand at the forefront of precision nanomedicine due to their structural versatility, tunable surface chemistry, and proven biocompatibility. Continued interdisciplinary research bridging materials science, biology, and clinical translation will pave the way for safe, effective, and personalized nanotherapeutics that can transform the future of disease diagnosis and targeted treatment.

Author contributions

The manuscript was written through the contributions of all authors. All authors have given approval to the final version of the manuscript. M. R. did formal literature review, analysis of data, and prepared the original draft. A. Y. did analysis of data and initial revision of the original manuscript. V. K. S. helped in data acquisition and analysis. S. P. supervised, edited and reviewed the final manuscript.

Conflicts of interest

There are no conflicts to declare.

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.

Acknowledgements

The authors would like to acknowledge the Central Instrument Facility (CIF) at IIT (BHU) Varanasi for providing the characterization facilities for this work. The authors are also thankful to Banasthali Vidyapith, Banasthali for providing the necessary research and infrastructure facilities.

References

1. W. Park and K. Na, Advances in the synthesis and application of nanoparticles for drug delivery, Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol., 2015, 7(4), 494–508.
2. 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.
3. Y. Zhuo, Y. G. Zhao and Y. Zhang, Enhancing drug solubility, bioavailability, and targeted therapeutic applications through magnetic nanoparticles, Molecules, 2024, 29(20), 4854.
4. O. Afzal, A. S. Altamimi, M. S. Nadeem, S. I. Alzarea, W. H. Almalki, A. Tariq and I. Kazmi, Nanoparticles in drug delivery: from history to therapeutic applications, Nanomater, 2022, 12(24), 4494.
5. N. Desai, Challenges in development of nanoparticle-based therapeutics, AAPS J., 2012, 14(2), 282–295.
6. M. J. Mitchell, M. M. Billingsley, R. M. Haley, M. E. Wechsler, N. A. Peppas and R. Langer, Engineering precision nanoparticles for drug delivery, Nat. Rev. Drug Discovery, 2021, 20(2), 101–124.
7. P. Das and N. R. Jana, Biomedical applications of functional polyaspartamide-based materials, ACS Appl. Polym. Mater., 2021, 3(10), 4791–4811.
8. P. Das, L. Albertazzi and J. O. Durand, Silica-Based Nanoparticles: From Understanding to Biomedical Applications, ACS Mater. Lett., 2025, 7(4), 1297–1312.
9. N. Shafiei, M. Nasrollahzadeh and S. Iravani, Green synthesis of silica and silicon nanoparticles and their biomedical and catalytic applications, Comments Inorg. Chem., 2021, 41(6), 317–372.
10. A. C. Kresge, M. E. Leonowicz, W. J. Roth, J. C. Vartuli and J. S. Beck, Ordered mesoporous molecular sieves synthesized by a liquid-crystal template mechanism, Nature, 1992, 359(6397), 710–712.
11. P. Jyothirmayi, A. Anusha, V. Sushma, V. Sirisha, K. Sravani and G. Nagalakshmi, Mesoporous silica nanoparticles as promising nano carriers-an overview, Eur. J. Pharm. Med. Res., 2024, 11(1), 121–129.
12. K. Djayanti, P. Maharjan, K. H. Cho, S. Jeong, M. S. Kim, M. C. Shin and K. A. Min, Mesoporous silica nanoparticles as a potential nanoplatform: therapeutic applications and considerations, Int. J. Mol. Sci., 2023, 24(7), 6349.
13. J. Cui, Y. Yan, Y. Wang and F. Caruso, Templated assembly of pH-labile polymer-drug particles for intracellular drug delivery, Adv. Funct. Mater., 2012, 22(22), 4718–4723.
14. M. Regí, F. Balas and D. Arcos, Mesoporous materials for drug delivery, Angew. Chem., Int. Ed., 2007, 46(40), 7548–7558.
15. I. I. Slowing, J. L. Vivero-Escoto, C. W. Wu and V. S. Y. Lin, Mesoporous silica nanoparticles as controlled release drug delivery and gene transfection carriers, Adv. Drug Deliv. Rev., 2008, 60(11), 1278–1288.
16. J. M. Rosenholm, C. Sahlgren and M. Lindén, Towards multifunctional, targeted drug delivery systems using mesoporous silica nanoparticles - opportunities & challenges, Nanoscale, 2009, 2(10), 1870–1883.
17. V. Mamaeva, C. Sahlgren and M. Lindén, Mesoporous silica nanoparticles in medicine-Recent advances, Adv. Drug Deliv. Rev., 2013, 65(5), 689–702.
18. J. G. Croissant, Y. Fatieiev and N. M. Khashab, Degradability and clearance of silicon, organosilica, silsesquioxane, silica mixed oxide, and mesoporous silica nanoparticles, Adv. Mater., 2017, 29(9), 1604634.
19. X. W. Lou, L. A. Archer and Z. Yang, Hollow micro-/nanostructures: synthesis and applications, Adv. Mater., 2008, 20(21), 3987–4019.
20. W. Stöber, A. Fink and E. Bohn, Controlled growth of monodisperse silica spheres in the micron size range, J. Colloid Interface Sci., 1968, 26(1), 62–69.
21. S. R. Kamath and A. Proctor, Silica gel from rice hull ash: preparation and characterization, Cereal Chem., 1998, 75(4), 484–487.
22. M. Rajotia and B. Sharma, A review on green approaches on waste to wealth strategies for biobutanol production, Adv. Drug Deliv. Rev., 2025, 21, 1–20.
23. A. Jain, R. Kushwaha, A. Sharma, M. Rajotia, V. K. Saroj and S. Panda, Synthesis and Characterizations of Mullite Based Glass–Ceramics from Agricultural Wastes, in International Conference on Advances in Glass and Glass-Ceramics, Springer Nature Singapore, Singapore, 2022, pp. 169–182.
24. R. A. Bakar, R. Yahya and S. N. Gan, Production of high purity amorphous silica from rice husk, Procedia Chem., 2016, 19, 189–195.
25. M. F. Anuar, Y. W. Fen, M. H. M. Zaid, K. A. Matori and R. E. M. Khaidir, The physical and optical studies of crystalline silica derived from the green synthesis of coconut husk ash, Appl. Sci., 2020, 10(6), 2128.
26. M. Gao, Q. Ma, Q. Lin, J. Chang and H. Ma, A novel approach to extract SiO2 from fly ash and its considerable adsorption properties, Mater. Des., 2017, 116, 666–675.
27. K. M. Jonathan, K. P. Kuria, G. J. Mwangi and N. F. Gichuki, Characterization of rice husk ash prepared by open air burning and furnace calcination, J. Chem. Eng. Mater. Sci., 2020, 11(2), 24–30.
28. M. F. Anuar, Y. W. Fen, M. H. M. Zaid, K. A. Matori and R. E. M. Khaidir, Synthesis and structural properties of coconut husk as potential silica source, Results Phys., 2018, 11, 1–4.
29. P. P. Nayak, S. Nandi and A. K. Datta, Comparative assessment of chemical treatments on extraction potential of commercial grade silica from rice husk, Eng. Rep., 2019, 1(2), e12035.
30. P. E. Imoisili, K. O. Ukoba and T. C. Jen, Green technology extraction and characterisation of silica nanoparticles from palm kernel shell ash via sol-gel, J. Mater. Res. Technol., 2020, 9(1), 307–313.
31. S. Hu and Y. L. Hsieh, Preparation of activated carbon and silica particles from rice straw, ACS Sustain. Chem. Eng., 2014, 2(4), 726–734.
32. T. Chanadee and S. Chaiyarat, Preparation and characterization of low cost silica powder from sweet corn cobs (Zea mays saccharata L.), J. Mater. Environ. Sci., 2016, 7(7), 2369–2374.
33. S. Rovani, J. J. Santos, P. Corio and D. A. Fungaro, Highly pure silica nanoparticles with high adsorption capacity obtained from sugarcane waste ash, ACS Omega, 2018, 3(3), 2618–2627.
34. M. Naddaf, H. Kafa and I. Ghanem, Extraction and characterization of nano-silica from olive stones, Silicon, 2020, 12(1), 185–192.
35. A. Pieła, E. Żymańczyk-Duda, M. Brzezińska-Rodak, M. Duda, J. Grzesiak, A. Saeid and M. Klimek-Ochab, Biogenic synthesis of silica nanoparticles from corn cobs husks. Dependence of the productivity on the method of raw material processing, Bioorg. Chem., 2020, 99, 103773.
36. H. Chang, J. Kim, W. Y. Rho, X. H. Pham, J. H. Lee, S. H. Lee, D. H. Jeong and B. H. Jun, Silica nanoparticles, in Nanotechnology for Bioapplications, Springer Singapore, Singapore, 2021, pp. 41–65.
37. H. Naaz, K. Rawat, P. Saffeullah and S. Umar, Silica nanoparticles synthesis and applications in agriculture for plant fertilization and protection: a review, Environ. Chem. Lett., 2023, 21(1), 539–559.
38. R. Epur, L. Minardi, M. K. Datta, S. J. Chung and P. N. Kumta, A simple facile approach to large scale synthesis of high specific surface area silicon nanoparticles, J. Solid State Chem., 2013, 208, 93–98.
39. M. Salavati-Niasari, J. Javidi and M. Dadkhah, Ball milling synthesis of silica nanoparticle from rice husk ash for drug delivery application, Comb. Chem. High Throughput Screen., 2013, 16(6), 458–462.
40. M. Savolainen, V. Touboltsev, P. Koppinen, K. P. Riikonen and K. Arutyunov, Ion beam sputtering for progressive reduction of nanostructures dimensions, Appl. Phys. A, 2004, 79(7), 1769–1773.
41. R. S. Fernandes, I. M. Jr and M. F. Pimentel, Revising the synthesis of Stöber silica nanoparticles: A multivariate assessment study on the effects of reaction parameters on the particle size, Colloids Surf., A, 2019, 577, 1–7.
42. Y. Huang, P. Li, R. Zhao, L. Zhao, J. Liu, S. Peng and Z. Zhang, Silica nanoparticles: Biomedical applications and toxicity, Biomed. Pharmacother., 2022, 151, 113053.
43. Z. A. Qiao, L. Zhang, M. Guo, Y. Liu and Q. Huo, Synthesis of mesoporous silica nanoparticles via controlled hydrolysis and condensation of silicon alkoxide, Chem. Mater., 2009, 21(16), 3823–3829.
44. K. D. Kim and H. T. Kim, Formation of silica nanoparticles by hydrolysis of TEOS using a mixed semi-batch/batch method, J. Sol-Gel Sci. Technol., 2002, 25(3), 183–189.
45. M. Barczak, Template removal from mesoporous silicas using different methods as a tool for adjusting their properties, New J. Chem., 2018, 42(6), 4182–4191.
46. R. Narayan, U. Y. Nayak, A. M. Raichur and S. Garg, Mesoporous silica nanoparticles: A comprehensive review on synthesis and recent advances, Pharmaceutics, 2018, 10(3), 118.
47. M. A. Tahan, M. Marwah, H. El-Zein, S. Tahan and L. Sanchez-Aranguren, Exploring mesoporous silica microparticles in pharmaceutical sciences: Drug delivery and therapeutic insights, Int. J. Pharm., 2025, 678, 125656.
48. L. Zhao, H. Qin, R. A. Wu and H. Zou, Recent advances of mesoporous materials in sample preparation, J. Chromatogr. A, 2012, 1228, 193–204.
49. Y. Wang, Q. Zhao, N. Han, L. Bai, J. Li, J. Liu and S. Wang, Mesoporous silica nanoparticles in drug delivery and biomedical applications. Nanomed, Nanomed. Nanotechnol. Biol. Med., 2015, 11(2), 313–327.
50. D. Ren, J. Xu, N. Chen, Z. Ye, X. Li, Q. Chen and S. Ma, Controlled synthesis of mesoporous silica nanoparticles with tunable architectures via oil-water microemulsion assembly process, Colloids Surf., A, 2021, 611, 125773.
51. T. Aubert, F. Grasset, S. Mornet, E. Duguet, O. Cador, S. Cordier and H. Haneda, Functional silica nanoparticles synthesized by water-in-oil microemulsion processes, J. Colloid Interface Sci., 2010, 341(2), 201–208.
52. R. Peng, M. A. Khan and C. L. Liu, Synthesis of Silica nanoparticles and their application of Dielectric relaxation spectroscopy-a review, Biomed. Pharmacother., 2023, 6, 101218.
53. M. A. Malik, M. Y. Wani and M. A. Hashim, Microemulsion method: A novel route to synthesize organic and inorganic nanomaterials: 1st Nano Update, Arab. J. Chem., 2012, 5(4), 397–417.
54. P. Randolph, R. R. Bansode, O. A. Hassan, D. J. Rehrah, R. Ravella, M. R. Reddy and M. Ahmedna, Effect of biochars produced from solid organic municipal waste on soil quality parameters, J. Environ. Manag., 2017, 192, 271–280.
55. S. Roy, R. Kumar, A. Acooli, S. Roy, A. Chatterjee, S. Chattaraj and S. K. Tripathy, Transforming nanomaterial synthesis through advanced microfluidic approaches: a review on accessing unrestricted possibilities, J. Compos. Sci., 2024, 8(10), 386.
56. J. Cheng, Y. Cheng, S. Jiang, J. Qiao, Y. Zhang, X. Zeng and P. Dong, Study of Influences on the Direct Electrolysis of Silica in Molten Salt: Particle Size, Temperature, Time, and Voltage, J. Electrochem. Energy Convers. Storage, 2023, 20(2), 021003.
57. S. Rezaei, I. Manoucheri, R. Moradian and B. Pourabbas, One-step chemical vapor deposition and modification of silica nanoparticles at the lowest possible temperature and superhydrophobic surface fabrication, Chem. Eng. J., 2014, 252, 11–16.
58. R. Peng, M. A. Khan, J. Wu and Z. Chen, In situ dielectric spectroscopy monitoring of silica nanoparticle synthesis in cationic water-in-oil microemulsions, Langmuir, 2022, 38(13), 4121–4128.
59. C. Wang, M. Wang, Y. Wang, J. Pan, C. Sun, Z. Zeng and X. Zhao, Construction and characterization of novel hydrophilic nanospheres loaded with lambda-cyhalothrin via ultrasonic emulsification–solvent evaporation, Int. J. Mol. Sci., 2022, 23(22), 14063.
60. S. D. Karande, S. A. Jadhav, H. B. Garud, V. A. Kalantre, S. H. Burungale and P. S. Patil, Green and sustainable synthesis of silica nanoparticles, Nanotechnol. Environ. Eng., 2021, 6(2), 29.
61. V. K. Yadav and M. H. Fulekar, Green synthesis and characterization of amorphous silica nanoparticles from fly ash, Mater. Today Proc., 2019, 18, 4351–4359.
62. W. Jansomboon, K. Boonmaloet, S. Sukaros and P. Prapainainar, Rice hull micro and nanosilica: synthesis and characterization, Key Eng. Mater., 2017, 718, 77–80.
63. P. Lu and Y. L. Hsieh, Highly pure amorphous silica nano-disks from rice straw, Powder Technol., 2012, 225, 149–155.
64. M. Rajotia, P. Pragya, P. Bajpai, A. Upadhyay, S. Mukherjee and S. Panda, Fabrication of Rice-Husk-Derived Silica Mediated Bioactive Glass for Antibacterial and Wound Healing Applications, ACS Sustain. Resource Manag., 2025, 2(2), 362–373.
65. K. Durairaj, P. Senthilkumar, P. Velmurugan, K. Dhamodaran, K. Kadirvelu and S. Kumaran, Sol-gel mediated synthesis of silica nanoparticle from Bambusa vulgaris leaves and its environmental applications: kinetics and isotherms studies, J. Sol-Gel Sci. Technol., 2019, 90(3), 653–664.
66. N. Jabeen, Q. Maqbool, S. Sajjad, A. Minhas, U. Younas, S. Anwaar and S. Z. Hussain, Biosynthesis and characterization of nano-silica as potential system for carrying streptomycin at nano-scale drug delivery, IET Nanobiotechnol., 2017, 11(5), 557–561.
67. N. Jaramillo, C. Paucar, A. Fernández, C. G. Negrete and C. García, Microemulsion assisted sol-gel method as approach to load a model anticancer drug inside silica nanoparticles for controlled release applications, Colloids Interface Sci. Commun., 2018, 24, 13–17.
68. C. C. Huang, W. Huang and C. S. Yeh, Shell-by-shell synthesis of multi-shelled mesoporous silica nanospheres for optical imaging and drug delivery, Biomaterials, 2011, 32(2), 556–564.
69. S. Prabha, D. Durgalakshmi, S. Rajendran and E. Lichtfouse, Plant-derived silica nanoparticles and composites for biosensors, bioimaging, drug delivery and supercapacitors: a review, Environ. Chem. Lett., 2021, 19(2), 1667–1691.
70. S. S. Latthe and A. V. Rao, Superhydrophobic SiO2 micro-particle coatings by spray method, Surf. Coat. Tech., 2012, 207, 489–492.
71. B. A. McCool, N. Hill, J. DiCarlo and W. J. DeSisto, Synthesis and characterization of mesoporous silica membranes via dip-coating and hydrothermal deposition techniques, J. Membr. Sci., 2003, 218(1–2), 55–67.
72. H. Ishikawa and T. Kikuchi, Preparation of transparent mesoporous silica films by a rapid solvent evaporation method, J. Mater. Chem., 1998, 8(8), 1783–1786.
73. B. M. Estevão, I. Miletto, N. Hioka, L. Marchese and E. Gianotti, Mesoporous silica nanoparticles functionalized with amino groups for biomedical applications, ChemistryOpen, 2021, 10(12), 1251–1259.
74. A. Liberman, N. Mendez, W. C. Trogler and A. C. Kummel, Synthesis and surface functionalization of silica nanoparticles for nanomedicine, Surf. Sci. Rep., 2014, 69(2–3), 132–158.
75. Y. He, L. Luo, S. Liang, M. Long and H. Xu, Amino-functionalized mesoporous silica nanoparticles as efficient carriers for anticancer drug delivery, J. Biomater. Appl., 2017, 32(4), 524–532.
76. S. Kralj, M. Drofenik and D. Makovec, Controlled surface functionalization of silica-coated magnetic nanoparticles with terminal amino and carboxyl groups, J. Nanopart. Res., 2011, 13(7), 2829–2841.
77. A. Matsumoto, K. Tsutsumi, K. Schumacher and K. K. Unger, Surface functionalization and stabilization of mesoporous silica spheres by silanization and their adsorption characteristics, Langmuir, 2002, 18(10), 4014–4019.
78. A. M. Putz, L. Almásy, A. Len and C. Ianăşi, Functionalized silica materials synthesized via co-condensation and post-grafting methods, Fuller. Nanotub. Car. N., 2019, 27(4), 323–332.
79. C. Liu, Y. Hu, L. Zhang and W. Yang, Controllable Synthesis of Amino-Functionalized Silica Particles via Co-condensation of Tetraethoxysilane and (3-Aminopropyl) triethoxysilane, Langmuir, 2024, 40(47), 25166–25172.
80. Y. Zhang, C. Y. Ang, M. Li, S. Y. Tan, Q. Qu, Z. Luo and Y. Zhao, Polymer-coated hollow mesoporous silica nanoparticles for triple-responsive drug delivery, ACS Appl. Mater. Interfaces, 2015, 7(32), 18179–18187.
81. S. A. Kulkarni, S. B. Ogale and K. P. Vijayamohanan, Tuning the hydrophobic properties of silica particles by surface silanization using mixed self-assembled monolayers, J. Colloid Interface Sci., 2008, 318(2), 372–379.
82. M. F. Morks, Fabrication and characterization of plasma-sprayed HA/SiO2 coatings for biomedical application, J. Mech. Behav. Biomed. Mater., 2008, 1(1), 105–111.
83. B. Akhavan, K. Jarvis and P. Majewski, Hydrophobic plasma polymer coated silica particles for petroleum hydrocarbon removal, ACS Appl. Mater. Interfaces, 2013, 5(17), 8563–8571.
84. A. Diacon, E. Rusen, A. Trifan, R. omoghi, O. Tutunaru, G. Crăciun and G. Voicu, Preparation of metal and metal oxide doped silica hollow spheres and the evaluation of their catalytic performance, Colloid Polym. Sci., 2020, 298(10), 1401–1410.
85. N. Erathodiyil and J. Y. Ying, Functionalization of inorganic nanoparticles for bioimaging applications, Acc. Chem. Res., 2011, 44(10), 925–935.
86. Z. Csőgör, M. Nacken, M. Sameti, C. M. Lehr and H. Schmidt, Modified silica particles for gene delivery, Mater. Sci. Eng. C., 2003, 23(1–2), 93–97.
87. V. Feldmann, J. Engelmann, S. Gottschalk and H. A. Mayer, Synthesis, characterization and examination of Gd [DO3A-hexylamine]-functionalized silica nanoparticles as contrast agent for MRI-applications, J. Colloid Interface Sci., 2012, 366(1), 70–79.
88. D. Gerion, J. Herberg, R. Bok, E. Gjersing, E. Ramon, R. Maxwell and F. F. Chen, Paramagnetic silica-coated nanocrystals as an advanced MRI contrast agent, J. Phys. Chem. C, 2007, 111(34), 12542–12551.
89. E. Ahmadi, N. Dehghannejad, S. Hashemikia, M. Ghasemnejad and H. Tabebordbar, Synthesis and surface modification of mesoporous silica nanoparticles and its application as carriers for sustained drug delivery, Drug Deliv., 2014, 21(3), 164–172.
90. V. Gubala, X. Le Guevel, R. Nooney, D. E. Williams and B. MacCraith, A comparison of mono and multivalent linkers and their effect on the colloidal stability of nanoparticle and immunoassays performance, Talanta, 2010, 81(4–5), 1833–1839.
91. N. Tsubokawa, H. Ichioka, T. Satoh, S. Hayashi and K. Fujiki, Grafting of ‘dendrimer-like’highly branched polymer onto ultrafine silica surface, React. Funct. Polym., 1998, 37(1–3), 75–82.
92. P. Singh, S. Srivastava and S. K. Singh, Nanosilica: Recent progress in synthesis, functionalization, biocompatibility, and biomedical applications, ACS Biomater. Sci. Eng., 2019, 5(10), 4882–4898.
93. S. Silviana and F. Dalanta, Advances in modified silica nanoparticles utilization for various applications: Now and future, E3S Web Conf., 2024, 503, 09004.
94. M. Florensa, M. Llenas, E. Medina-Gutierrez, S. Sandoval and G. Tobias-Rossell, Key parameters for the rational design, synthesis, and functionalization of biocompatible mesoporous silica nanoparticles, Pharmaceutics, 2022, 14(12), 2703.
95. T. B. Asafa, O. Adedokun and T. T. Dele-Afolabi, Characterization techniques in nanotechnology: the state of the art, Microb. Nanobiotechnol. Prin. Appl., 2021, 18, 21–73.
96. U. E. Ewii, A. L. Onugwu, V. C. Nwokpor, I. A. Akpaso, T. E. Ogbulie, B. Aharanwa, C. Chijioke, N. Verla, C. Iheme, C. Ujowundu and C. Anyiam, Novel drug delivery systems: Insight into self-powered and nano-enabled drug delivery systems, Nano TransMed, 2024, 3, 100042.
97. T. Fontecave, C. Boissiere, N. Baccile, F. J. Plou and C. Sanchez, Using evaporation-induced self-assembly for the direct drug templating of therapeutic vectors with high loading fractions, tunable drug release, and controlled degradation, Chem. Mat., 2013, 25(23), 4671–4678.
98. Z. Yi, L. F. Dumée, C. J. Garvey, C. Feng, F. She, J. E. Rookes and L. Kong, A new insight into growth mechanism and kinetics of mesoporous silica nanoparticles by in situ small angle X-ray scattering, Langmuir, 2015, 31(30), 8478–8487.
99. M. Manzano and M. Regí, Mesoporous silica nanoparticles for drug delivery, Adv. Funct. Mater., 2020, 30(2), 1902634.
100. M. J. Hollamby, D. Borisova, P. Brown, J. Eastoe, I. Grillo and D. Shchukin, Growth of mesoporous silica nanoparticles monitored by time-resolved small-angle neutron scattering, Langmuir, 2012, 28(9), 4425–4433.
101. K. J. Edler, Current understanding of formation mechanisms in surfactant-templated materials, Aust. J. Chem., 2005, 58(9), 627–643.
102. P. Prabhakar and M. Banerjee, Nanotechnology in drug delivery system: Challenges and opportunities, Int. J. Pharm. Sci. Res., 2020, 12(4), 492–498.
103. N. Parvin, S. W. Joo and T. K. Mandal, Biodegradable and stimuli-responsive nanomaterials for targeted drug delivery in autoimmune diseases, J. Funct. Biomater., 2025, 16(1), 24.
104. P. Jaiswal, B. Gidwani and A. Vyas, Nanostructured lipid carriers and their current application in targeted drug delivery, Artif. Cells, Nanomed. Biotechnol., 2016, 44(1), 27–40.
105. V. Shafiei-Irannejad, N. Samadi, R. Salehi, B. Yousefi, M. Rahimi, A. Akbarzadeh and N. Zarghami, Reversion of multidrug resistance by co-encapsulation of doxorubicin and metformin in poly (lactide-co-glycolide)-d-α-tocopheryl polyethylene glycol 1000 succinate nanoparticles, Pharm. Res., 2018, 35(6), 119.
106. B. Xu, S. Li, R. Shi and H. Liu, Multifunctional mesoporous silica nanoparticles for biomedical applications, Sig. Transduct. Target. Ther., 2023, 8(1), 435.
107. N. Kaushik, S. B. Borkar, S. K. Nandanwar, P. K. Panda, E. H. Choi and N. K. Kaushik, Nanocarrier cancer therapeutics with functional stimuli-responsive mechanisms, J. Nanobiotechnol., 2022, 20(1), 152.
108. P. Panja, P. Das, K. Mandal and N. R. Jana, Hyperbranched polyglycerol grafting on the surface of silica-coated nanoparticles for high colloidal stability and low nonspecific interaction, ACS Sustain. Chem. Eng., 2017, 5(6), 4879–4889.
109. R. Khoz, F. Yazdian, M. Pourmadadi, A. Rahdar, S. Fathi-karkan and S. Pandey, Current trends in silica-based drug delivery systems, Eur. J. Med. Chem. Rep, 2024, 12, 100206.
110. L. Zhang, Y. Fan, Z. Yang, C. Y. Wong and M. Yang, A novel reactive oxygen species nano-amplifier for tumor-targeted photoacoustic imaging and synergistic therapy, J. Colloid Interface Sci., 2025, 681, 331–343.
111. C. Y. Zhao, R. Cheng, Z. Yang and Z. M. Tian, Nanotechnology for cancer therapy based on chemotherapy, Molecules, 2018, 23(4), 826.
112. P. Das, S. Pujals, L. M. Ali, M. Gary-Bobo, L. Albertazzi and J. O. Durand, Super-resolution imaging of antibody-conjugated biodegradable periodic mesoporous organosilica nanoparticles for targeted chemotherapy of prostate cancer, Nanoscale, 2023, 15(28), 12008–12024.
113. S. Theivendran, S. Lazarev and C. Yu, Mesoporous silica/organosilica nanoparticles for cancer immunotherapy, Explorations, 2023, 3(3), 20220086.
114. Z. Cao, J. Liu and X. Yang, Deformable nanocarriers for enhanced drug delivery and cancer therapy, Explorations, 2024, 4(5), 20230037.
115. R. Heidari, V. Assadollahi, P. Khosravian, S. A. Mirzaei and F. Elahian, Engineered mesoporous silica nanoparticles, new insight nanoplatforms into effective cancer gene therapy, Int. J. Biol. Macromol., 2023, 253, 127060.
116. M. Kulkarni, K. Patel, A. Patel, S. Patel, J. Desai, M. Patel and N. Solanki, Nanomaterials as drug delivery agents for overcoming the blood–brain barrier: A comprehensive review, ADMET and DMPK, 2024, 12(1), 63–105.
117. C. Das, D. Chakraborty and N. K. Mondal, Silica Nanoparticle for the Treatment of Bacterial Infections, in Emerging Sustainable Nanomaterials for Biomedical Applications, Springer Nature Switzerland, Cham, 2024, pp. 65–87.
118. S. Yang, X. Han, Y. Yang, H. Qiao, Z. Yu, Y. Liu and T. Tang, Bacteria-targeting nanoparticles with microenvironment-responsive antibiotic release to eliminate intracellular Staphylococcus aureus and associated infection, ACS Appl. Mater. Interfaces, 2018, 10(17), 14299–14311.
119. F. Herranz, E. Almarza, I. Rodríguez, B. Salinas, Y. Rosell, M. Desco and J. Cabello, The application of nanoparticles in gene therapy and magnetic resonance imaging, Microsc. Res. Tech., 2011, 74(7), 577–591.
120. Y. S. Lin and C. L. Haynes, Impacts of mesoporous silica nanoparticle size, pore ordering, and pore integrity on hemolytic activity, J. Am. Chem. Soc., 2010, 132(13), 4834–4842.
121. T. M. Albayati, S. M. Alardhi, A. H. Khalbas, Z. J. Humdi, N. S. Ali, I. K. Salih, N. M. Saady, S. Zendehboudi and M. A. Abdulrahman, Comprehensive review of mesoporous silica nanoparticles: drug loading, release, and applications as hemostatic agents, ChemistrySelect, 2024, 9(23), e202400450.
122. H. Duan, L. Wang, S. Wang and Y. He, Surface modification potentials of cell membrane-based materials for targeted therapies: a chemotherapy-focused review, Nanomedicine, 2023, 18(19), 1281–1303.
123. M. Joglekar, R. A. Roggers, Y. Zhao and B. G. Trewyn, Interaction effects of mesoporous silica nanoparticles with different morphologies on human red blood cells, RSC Adv., 2013, 3(7), 2454–2461.
124. S. Mukhopadhyay, H. Veroniaina, T. Chimombe, L. Han, W. Zhenghong and Q. Xiaole, Synthesis and compatibility evaluation of versatile mesoporous silica nanoparticles with red blood cells: an overview, RSC Adv., 2019, 9(61), 35566–35578.
125. X. Cheng, Q. Xie and Y. Sun, Advances in nanomaterial-based targeted drug delivery systems, Front. Bioeng. Biotechnol., 2023, 11, 1177151.
126. D. Bhavsar, V. Patel and K. Sawant, Systematic investigation of in vitro and in vivo safety, toxicity and degradation of mesoporous silica nanoparticles synthesized using commercial sodium silicate, Micropor. Mesopor. Mat., 2019, 284, 343–352.
127. V. Rabolli, L. C. Thomassen, C. Princen, D. Napierska, L. Gonzalez, M. Kirsch-Volders and D. Lison, Influence of size, surface area and microporosity on the in vitro cytotoxic activity of amorphous silica nanoparticles in different cell types, Nanotoxicology, 2010, 4(3), 307–318.
128. X. Dong, Z. Wu, X. Li, L. Xiao, M. Yang, Y. Li, J. Duan and Z. Sun, The size-dependent cytotoxicity of amorphous silica nanoparticles: a systematic review of in vitro studies, Int. J. Nanomedicine, 2020, 9089–9113.
129. L. Chen, J. Liu, Y. Zhang, G. Zhang, Y. Kang, A. Chen and L. Shao, The toxicity of silica nanoparticles to the immune system, Nanomedicine, 2018, 13(15), 1939–1962.

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