Facile synthesis of tunable zinc–adenine frameworks for aptamer-based biological applications

Abstract

Zinc-based metal–organic frameworks (ZnMOFs) have attracted significant attention in bioanalytical and biomedical applications owing to their structural tunability, biocompatibility, and potential for integration with molecular recognition elements. In this study, we report a facile aqueous synthesis of ZnMOFs using adenine as a nucleobase linker and explore their multifunctionality for aptamer-based biological applications. Density functional theory calculations revealed Zn–N coordination and Zn–cluster formation underpinning the inherently amorphous framework architecture. The resulting amorphous ZnMOF particles exhibited a controllable size and tunable surface charge through post-synthesis treatments such as polystyrene sulfonate treatment and sonication. Notably, the system enables direct incorporation of aptamers via their poly-adenine tails without post-synthesis biofunctionalization steps. Incorporation of ZnMOFs with a VCAM-1 aptamer enhanced fluorescence signals in the immunofluorescence assay and flow cytometry, providing a sensitive platform for biomolecular detection. Additionally, ZnMOFs decorated with a CD63 aptamer enabled selective exosome capture with gentle recovery, maintaining the biomarker's integrity for downstream quantitative reverse transcriptase loop-mediated isothermal amplification (qRT-LAMP) of exosomal RNA. Collectively, our findings establish ZnMOFs as simple, versatile, and tunable platforms for aptamer-based sensing and exosome isolation, with broad potential for biological and biomedical applications.

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1. Introduction

Metal–organic frameworks (MOFs) are a class of hybrid materials formed by the coordination of metal ions with organic ligands. Their modularity and crystallinity allow exquisite control over surface chemistry, pore architecture, and chemical functionality.¹ Over the past decade, MOFs have transitioned their applications from gas storage and catalysis to various biomedical domains. Among these materials, zinc-based MOFs (ZnMOFs) have emerged as particularly attractive candidates for biological applications, given the biocompatibility of zinc and the ability to functionalize the framework with biologically relevant molecules.^2–5 These unique features make ZnMOFs promising materials for applications such as drug delivery, biosensing, and molecular recognition. Several recent studies have explored ZnMOFs as biological scaffolds with tailored coordination environments and functional interfaces. Bio-MOF-1^6–10 and Bio-MOF-2^11,12 are two well-known examples of biocompatible ZnMOFs that have been specifically designed for biological applications. Additionally, adenine-based Bio-MOFs have demonstrated how nucleobase chemistry can be harnessed to mimic natural base-pairing interactions.¹³ Beyond nucleic-acid recognition, ZnMOFs have also been explored for their porosity, hydrophilicity, and guest-responsive behaviours.^14,15 These studies predominantly focus on crystalline frameworks with long-range order, defined pore structures, and ligand coordination motifs optimized through controlled synthesis. However, the synthesis process of these MOFs is inherently intricate, involving precise control over solvothermal reaction conditions including temperature, solvents, and reactant concentrations.

Aptamers, short single-stranded oligonucleotides capable of binding specific targets with high affinity, have been increasingly incorporated into nanomaterials for targeted technologies.^16–19 Aptamers function similarly to antibodies but offer advantages such as smaller size, higher stability and low-cost chemical synthesis. Aptamer-functionalized MOFs combine the selective binding properties of aptamers with the structural versatility of MOFs, creating multifunctional materials for bioanalytical and therapeutic purposes.^20,21

Here, we report a facile synthesis of zinc–adenine MOFs under aqueous, room-temperature conditions, followed by post-synthesis treatments to tailor particle size and surface charge. Using density functional theory, we elucidate the Zn–N coordination motif and the amorphous tendency of ZnMOFs at high Zn : adenine molar ratios. Moreover, the presence of poly-adenine tails in aptamers enables direct co-assembly of aptamers into the MOF architecture, providing a simple, one-step synthesis of biofunctional materials without chemical conjugation. We then demonstrate the versatility of ZnMOFs in two remarkable aptamer-based applications: (i) incorporation of the VCAM-1 aptamer to enhance the fluorescence signal in immunofluorescence assays and flow cytometry, and (ii) incorporation of the CD63 aptamer for selective exosome capture and recovery, with downstream mRNA biomarker analysis using loop-mediated isothermal amplification (LAMP). These results position ZnMOFs as practically adaptable, multifunctional platforms for translational bioanalysis.

2. Results and discussion

Formation, structural characterization, and tunability of Zn–adenine MOFs

First, we studied the spontaneous formation of the MOFs between zinc and different nucleobases. After mixing zinc sulphate with different nucleobases (A, T, C, U), white precipitates quickly appeared in all cases (Fig. 1A). However, UV-vis spectroscopic analysis of supernatant fractions and resuspended pellets revealed that only adenine was incorporated into the pellets (Fig. 1B and C). This selectivity can possibly be explained by the distinct coordination and structural features of purine versus pyrimidine nucleobases. Adenine, as a purine, contained four Lewis-basic nitrogen sites (N1, N3, N7, and N9) arranged within a rigid bicyclic scaffold, enabling multidentate and bridging coordination to Zn²⁺. Such a geometry supports the formation of extended Zn–adenine clusters that readily precipitate as a coordination network in water. In contrast, the pyrimidine nucleobases (cytosine, uracil, and thymine) contain fewer donor nitrogens and possess electron-withdrawing carbonyl groups that reduce ligand basicity and favour strong hydration, preventing their incorporation into the insoluble fractions. Therefore, we only used adenine as the nucleobase for the zinc MOF (ZnMOF) in later applications. A titration study showed that under our experiment conditions, the atomic ratio (Zn : adenine) was 2 : 1 (Fig. 1D), which was in agreement with a previous study.⁴ UV spectral analysis showed a blue shift in peak absorbance of the ZnMOF compared with free adenine (Fig. 1E), suggesting π–π* electronic transitions in our conjugated system.

Fig. 1 Spontaneous formation of Zn–adenine metal–organic frameworks (ZnMOF) and modulation of their colloidal properties. (A) Different nucleobases (A, T, C, U) were added to the ZnSO₄ solution, forming white precipitates. (B) and (C) UV-vis analysis of supernatant and pellet fractions showing that only adenine was incorporated into the ZnMOF. (D) Titration study determined the stoichiometric ratio of zinc ions to adenine molecules. (E) Comparison of adenine and ZnMOF UV-vis spectra. (F) Local coordination structures within the amorphous Zn–adenine framework were explored using density functional theory (DFT) calculations to propose plausible Zn–N bonding motifs: (i) amorphous structure presented in periodic unit cells. The formation of Zn clusters is highlighted by red circles; (ii) top view and (iii) side view of the ZnMOF (big light blue balls represent Zn atoms while blue, grey and white small balls represent N, C and H atoms, respectively). (G) TEM images of the native ZnMOF and post-synthesis treatments. (H) Particle size distribution and (I) zeta-potential measurements of ZnMOF particles.

Density functional theory (DFT) calculations revealed more structural information for the as-synthesized ZnMOF material. DFT calculations were performed using the Vienna ab initio simulation package (VASP).^22,23 Spin-polarized calculations were conducted using the Perdew–Burke–Ernzerhof (PBE) exchange–correlation functional within the generalized gradient approximation.²⁴ A plane-wave cut-off energy of 520 eV was applied, and Gaussian smearing with a width of 0.01 eV was used. Structural optimizations were carried out using the conjugate-gradient algorithm within a 20 Å × 20 Å × 20 Å simulation cell, and Brillouin zone sampling was performed using a Γ-centered k-point grid. Zn atoms preferred to coordinate with N atoms of the adenine, as was also reported in an earlier study.²⁵ We observed that the atomic ratio Zn : adenine = 1 : 1 was not enough to crystallize the ZnMOF (Fig. S1, SI). For structures with the Zn : adenine ratio larger than 1 (such as the Zn : adenine atomic ratio = 13 : 8, Fig. 1F), some Zn atoms are clustered together, inducing the amorphous structure of the ZnMOF.

Fig. 1G–I show different post-synthesis treatment methods for modulating the ZnMOF particle size and zeta potential, using polystyrene sulfonate (PSS) treatment and sonication. Compared to the native particles, PSS treatment alone reduced the particle size to around 1 µm. Further sonication reduced the particle size to below 200 nm, which could be employed for in vivo applications. The treatment of PSS shifts the particle zeta potential of ZnMOF particles from neutral to negative charges, which is critically important for biological applications. In this paper, we employed 1 µm ZnMOF microparticles, as they are easier to collect and handle with centrifugation than sub-200 nm particles.

Aptamer incorporation and coordination mechanism

Next, we investigated the inclusion of a fluorescence-tagged VCAM-1 aptamer into the ZnMOF. The presence of the aptamer's poly-adenine tailing facilitated its incorporation into the MOF structure (Fig. 2A). Fluorescence quantification of the supernatant fraction showed that the majority of aptamers were readily incorporated into the particles (Fig. 2B). Flow cytometry analysis further confirmed the incorporation of aptamers into particles (Fig. 2C) and their potential in this application. The inclusion of aptamers into the ZnMOF did not significantly alter the particle size or zeta potential (Fig. 2D and E). The particles are stable for several days post-synthesis, with negligible changes in the size and zeta-potential (Fig. 2F).

Fig. 2 Decoration of the ZnMOF with fluorescence-tagged VCAM-1 aptamer. (A) Schematic representation of spontaneous formation of ZnMOF with aptamers. (B) Fluorescence images of reaction tubes before (top) and after (bottom) centrifugation to collect aptamer@ZnMOF. (C) Flow cytometry analysis of particles. (D) Dynamic light scattering and (E) Zeta-potential analysis of aptamer@ZnMOF. (F) Particle colloidal properties over 5 days post-synthesis. (G) Structure of the ZnMOF coordinated with the VCAM-1 aptamer obtained from DFT calculations: (i) structure in periodic unit cells, the adenine molecules of the ZnMOF substrate are presented in stick mode for easier visualization; (ii) top view and (iii) side view of the ZnMOF. Color code: big light blue balls represent Zn atoms while blue, grey and white small balls represent N, C and H atoms, respectively. The formation of a “Zn bridge” between the VCAM-1 aptamer and the ZnMOF substrate is highlighted by red circles in Fig. 2G(iii).

Due to the precipitation and amorphous nature of the Zn–adenine coordination network, techniques requiring soluble or crystalline samples (such as nuclear magnetic resonance titration or single-crystal X-ray diffraction) are not applicable in characterizing this system. DFT calculations were used to propose plausible coordination interactions between the aptamer and the amorphous ZnMOF network, highlighting potential Zn-bridge formation within the local coordination environment (Fig. 2G). Using the structure including three adenine fragments with a sugar-phosphate backbone to mimic the tail of the DNA aptamer, DFT optimization revealed the coordination between the ZnMOF and the VCAM-1 aptamer via the formation of “Zn bridges”, which are highlighted in Fig. 2G(iii). In this structure, the Zn : adenine atomic ratio = 16 : 8, matching very well with the titration results of the Zn : adenine atomic ratio = 2 in Fig. 1D. Furthermore, the formation of stable “Zn bridges” in the ZnMOF-aptamer is also consistent with the stability test of the material as observed in Fig. 2F. It is important to note that the ZnMOF synthesized under the present aqueous conditions exhibits an amorphous architecture rather than a long-range ordered crystalline framework. The DFT models therefore represent energetically favorable local coordination environments and Zn–N bonding motifs, rather than a periodic crystal lattice. These proposed local structures are consistent with the experimentally determined Zn : adenine stoichiometry, particle stability, and functional aptamer incorporation efficiency. Although simplified, this model captures the essential coordination interactions and aligns with both the experimentally measured 2 : 1 Zn : A ratio and the high aptamer incorporation efficiency. These results together strongly suggested that aptamer-incorporation could be achieved via a coordination-driven, one-step process without post-synthesis chemical conjugation.

Signal-amplified cellular staining with VCAM-1 aptamer@ZnMOF

We then proceed with using the fluorescence-tagged VCAM-1 aptamer@ZnMOF in an immunofluorescent microscopy assay. Hypoxia and lipopolysaccharide (LPS) stimulation was applied to SVEC4-10 endothelial cells to induce VCAM-1 overexpression, as both conditions mimic pathological features associated with myocardial infarction.^26–30 In particular, hypoxia reflects oxygen deprivation during ischemic injury, whereas LPS triggers endothelial inflammation and vascular activation similar to post-infarction inflammatory responses. As can be seen in Fig. 3A, endothelial cells stimulated with hypoxia or LPS exhibited markedly stronger fluorescence when stained with VCAM-1 aptamer@ZnMOF compared with a free fluorescent aptamer. This enhancement arises from the multivalent display of fluorophores on each ZnMOF particle, which effectively concentrates the fluorescent signal from multiple aptamer strands into a single binding event rather than relying on one fluorophore per free aptamer strand (Fig. 3B).

Fig. 3 Application of the ZnMOF in cell staining. (A) SVEC4-10 endothelial cells were cultured in either hypoxia or lipopolysaccharide (LPS) conditions and stained with either the VCAM-1 aptamer or VCAM-1 aptamer@ZnMOF in an immunofluorescent assay (scale bar = 50 µm). (B) Schematic representation of signal amplification with fluorescent-tagged aptamer@ZnMOF. (C) Representative whole-well fluorescence imaging of a 12-well plate with a Sapphire FL Biomolecular Imager. (D) Quantification of the fluorescence signal. (E) Flow cytometry demonstrating enhanced signal resolution with fluorescence-tagged aptamer@ZnMOF.

To evaluate performance in high-throughput assay formats, whole-well fluorescence imaging was conducted (Fig. 3C and D). In these measurements, the signal obtained from VCAM-1 aptamer@ZnMOF staining was significantly higher across the entire well surface, yielding improved contrast between stimulated and control samples. This is particularly advantageous for applications that rely on plate readers or automated imaging systems, where global fluorescence intensity rather than single-cell resolution often dictates assay sensitivity. The enhanced well-wide signal demonstrates that ZnMOF-mediated fluorophore clustering greatly improves the detectability of VCAM-1 in population-level measurements, reducing the influence of cellular heterogeneity.

Flow cytometry analysis also benefited from this signal amplification strategy with clearer resolution using VCAM1-aptamer@ZnMOF staining (Fig. 3E). Endothelial cells activated by hypoxia or LPS and stained with aptamer@ZnMOF exhibited a pronounced rightward shift in fluorescence intensity, resulting in better separation between sample groups. Overall, using the ZnMOF as an aptamer scaffold transforms fluorescently labelled aptamers into a highly multivalent, signal-amplifying probe, thereby enhancing sensitivity across microscopy, well-plate imaging, and flow cytometry.

Exosome isolation with CD63 aptamer@ZnMOF

Another important application of our particles is the selective enrichment of exosomes by incorporating the CD63 aptamer. We also employed a reverse complement oligonucleotide (RVseq) for the release of the bound vesicles (Fig. 4A). As shown in Fig. 4B, CD63 aptamer@ZnMOF effectively depleted exosomes from the input sample, and RVseq oligo partially released exosomes from MOF particles. We further optimized the exosome capture time (Fig. 4C) and the RVseq oligo concentration (Fig. 4D) for maximal recovery of exosomes. The optimal conditions were determined to be a 4 h incubation for exosome capture and a 5 µM RVseq oligonucleotide for efficient vesicle release, which were subsequently used in all later experiments. Traditional immunoaffinity isolation techniques often use harsh conditions such as extreme pH or high salinity to elute bound antigens. Since exosomes are more stable in neutral pH solutions compared to acidic conditions,³¹ our gentle method is favoured for exosome enrichment and processing. The rescued exosomes were confirmed to express endosomal markers (CD63 and CD9) and negative for markers of other sub-cellular compartments (Fig. 4E), showcasing the selectivity of our exosome isolation platform.

Fig. 4 Decoration of the ZnMOF with the CD63 aptamer for exosome isolation. (A) Schematic illustration of exosome capture with CD63 aptamer@ZnMOF and release using the reverse complement oligonucleotide (RVseq oligo). (B) Representative NTA profiles of input, unbound, and rescued exosomes. (C) Optimization of the exosome capture time. (D) Optimization of the RVseq concentration for efficient recovery. (E) Western blot analysis of rescued exosomes, showing enrichment of CD63 and CD9, and the absence of calnexin and cytochrome c (CL: cell lysates, RE: rescued exosome). (F) Representative amplification curves and (G) quantification of the exosomal ALPL mRNA biomarker using quantitative real-time Loop-mediated isothermal amplification (qRT-LAMP) (NO: normoxic culture, HO: hypoxic culture, LPS: lipopolysaccharide-treated SVEC4-10 culture, **p < 0.01, ***p < 0.001). (H) Schematic workflow for exosome isolation from human serum followed by qRT-LAMP analysis. (I) Representative qRT-LAMP amplification curves and quantification (inset) of exosomal ALPL mRNA in spiked serum and healthy serum, ***p < 0.001.

Quantitative reverse transcriptase loop-mediated isothermal amplification (qRT-LAMP) analysis of ALPL mRNA (a tentative biomarker of acute myocardial infarction³²) was carried out to determine whether the rescued exosome could be used for the further downstream process of biomarker detection. As shown in Fig. 4F and G, exosomes derived from hypoxia- or LPS-stimulated SVEC4-10 endothelial cells exhibited significantly elevated ALPL transcript levels compared with those from normoxic cells. This finding suggests that under ischemic and inflammatory stress, ALPL expression is upregulated, reflecting endothelial activation and potential remodelling processes relevant to myocardial infarction.

To further demonstrate the translational potential of our platform, we next applied it to human serum samples (Fig. 4H). Serum was obtained from a healthy donor (male, 32-year old) and spiked with exosomes from LPS-activated SVEC4-10 cell culture to mimic disease conditions. Exosomes were then isolated from serum using CD63 aptamer@ZnMOF and subsequently analyzed for ALPL mRNA by qRT-LAMP. As shown in Fig. 4I, the spiked serum exhibited a pronounced amplification signal compared to healthy serum. When the CD63 aptamer was replaced with a scramble aptamer, there was no amplification, confirming the specificity of our detection process. These results underscore the sensitivity of our platform for detecting exosome-derived mRNA biomarkers within complex biofluid matrices. Collectively, the data demonstrate that CD63 aptamer–decorated ZnMOFs enable efficient and selective exosome enrichment under mild conditions, preserve vesicle biomarker quality, and facilitate downstream molecular analyses in both experimental and clinically relevant contexts.

3. Conclusions

In addition to highly crystalline frameworks, increasing attention has been directed toward amorphous MOFs, which retain extended metal–ligand coordination networks but lack long-range structural periodicity.^33,34 Amorphous MOFs often exhibit structural disorder arising from kinetic growth conditions, high metal-to-ligand ratios, or rapid precipitation processes, consistent with the mechanisms described for directly synthesized amorphous coordination polymers and amorphous MOFs under ambient, aqueous conditions.³⁵ Importantly, this structural flexibility can be advantageous in biological applications, where aqueous synthesis, surface adaptability, and dynamic coordination environments are preferred over rigid lattice order. Amorphous MOFs have therefore emerged as promising platforms for biomolecule incorporation, sensing, and biointerfacing, particularly when mild synthesis conditions and colloidal stability are preferred over rigid lattice order.

In this work, we developed a facile aqueous synthesis of ZnMOF using adenine as a nucleobase, resulting in tunable particles that exhibit advantageous properties for biological applications. Unlike conventional crystalline Bio-MOFs that require solvothermal synthesis or complex ligand design, our platform forms spontaneously in water and enables direct incorporation of aptamers through their poly-adenine tails. Our results demonstrated that post-synthesis treatments, including polystyrene sulfonate (PSS) and sonication, can be employed to modulate the size and surface charge of the ZnMOF particles. Through density functional theory calculations, we elucidated the atomic-level coordination of Zn–adenine networks and the role of Zn clustering in the amorphous framework architecture. By avoiding organic solvents, harsh reaction conditions, and multi-step conjugation chemistries, this platform offers a practical and versatile approach for developing bio-functional materials.

The key innovation of this platform lies in the direct incorporation of aptamers via poly-adenine tails during particle formation, eliminating the need for post-synthesis chemical conjugation. This one-step synthesis and functionalization strategy enabled the creation of multifunctional bioactive particles without harsh reaction conditions. We demonstrate that the simple incorporation of aptamers, such as VCAM-1 and CD63 aptamers, into ZnMOF particles enabled the development of bio-functional materials with enhanced capabilities in immunofluorescence assays, flow cytometry and exosome isolation. Functionally, VCAM-1 aptamer@ZnMOF demonstrated multivalent signal amplification in immunofluorescence assays and flow cytometry, providing improved detection sensitivity under hypoxic and inflammatory endothelial activation models. Furthermore, CD63 aptamer@ZnMOF enabled selective exosome enrichment and gentle release using reverse complement oligonucleotides, preserving vesicle integrity for downstream molecular analysis. Successful detection of ALPL mRNA via qRT-LAMP in both cell culture-derived and serum-spiked samples highlights the translational potential of this platform. Although exosomal nucleic acids have been widely reported as disease specific biomarkers,³⁶ it remains critical to isolate EVs under conditions that preserve their molecular cargo. Our ZnMOF platform achieves this by gently enriching EVs while maintaining the integrity of their nucleic acid contents for downstream analysis. This strategy aligns with our previously published terbium coordination-polymer system, which also enabled selective exosome isolation under mild conditions.³⁷ Our studies collectively highlight a developing concept that coordination polymers and MOF-like materials can serve as a gentle, modular, and biologically compatible class of scaffolds for EV enrichment and molecular analysis.

In conclusion, this work establishes amorphous Zn–adenine coordination materials as versatile, tunable, and biologically compatible scaffolds for aptamer-based labelling and exosome isolation. The ability to customize particle physio-chemical properties and aptamer selection highlighted ZnMOFs as promising candidates for next-generation diagnostic platforms. Future work could focus on optimizing ZnMOF formulations for in vivo applications and expanding their use in other bioanalytical techniques.

Author contributions

CMN: investigation, methodology, formal analysis, data curation, validation, visualization, writing – original draft preparation, and review and editing; QTT: investigation, methodology, and writing – review and editing; NTN: supervision and writing – review and editing; and HTT: supervision and writing – review and editing.

Conflicts of interest

The authors declare no competing interests.

Data availability

All the relevant data of this study are available within the manuscript and its supplementary information (SI). The supplementary information file includes detailed Materials and Methods, as well as supplementary tables and figures containing the oligonucleotide sequences used in this study, the optimized Zn–adenine coordination structures from DFT calculations, the adenine calibration curve, and the qRT-LAMP calibration curve. See DOI: https://doi.org/10.1039/d6qm00114a.

Acknowledgements

The author thanks Dr Yuao Wu (Griffith University) for the help with TEM imaging. CMN was supported by the Griffith University Higher Degree Research Scholarship. HTT acknowledges funding from the National Heart Foundation (102761) and the National Health and Medical Research Council (APP2002827).

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