This review focuses on stimuli‐responsive and novel MOF systems that can deliver drugs in response to pH, redox reactions, enzymes, light, magnetic fields, and other biological stimuli to treat diseases.
Abstract
Due to their exceptional porosity, structural versatility, and modular coordination chemistry, metal–organic frameworks (MOFs) have emerged as versatile platforms for targeted drug delivery. These structures enable fine‐tuning of pore size, surface activity, and framework stability for the encapsulation of a broad range of therapeutics, including small‐molecule drugs and biomacromolecules such as nucleic acids, proteins, and peptides. In this review, the main principles governing MOF formation, drug encapsulation strategies, and molecular interactions that control host–guest behavior are described in detail. This review focuses on stimuli‐responsive and novel MOF systems that can deliver drugs in response to pH, redox reactions, enzymes, light, magnetic fields, and other biological stimuli to treat diseases. Other hybrid and composite systems, including those with polymers, lipids, hydrogels, and inorganic nanoparticles, are also discussed here. This work examined how these multifunctional systems can be enhanced in terms of their stability, targeting capabilities, and therapeutic potential. The main treatment applications, including anticancer, antimicrobial, anti‐inflammatory, cardiovascular, and gene delivery, are discussed, including synergistic interventions and combination therapies. Important factors involved in biocompatibility, toxicity, pharmacokinetics, and biodegradation are examined to assess the translational potential of MOF‐based therapeutics. Current challenges and limitations are identified, and future directions are addressed, including computationally guided and bioinspired designs, immune‐evasive coatings, theranostic MOFs, and eco‐friendly and scalable manufacturing. Overall, these results highlight the potential of MOFs for drug delivery. Their amenability to modifications and their unique tunability, multimodality, and intelligent responsiveness make them promising candidates for precision medicine and advanced therapeutic strategies.
As cutting-edge porous materials, the properties of metal–organic frameworks (MOFs) are governed by their metal nodes and organic linkers, as well as the assembly mode of these subunits. This allows the loading capacity of MOFs for small-molecule drugs to be readily tailored by rationally adjusting their structures and physicochemical properties. Furthermore, the introduction of additional functional groups into MOFs can enable the stimuli-responsive release of small-molecule drugs, thus rendering MOFs promising candidates for small-molecule drug delivery. With this perspective, we summarize the advances in the construction of MOF-based small-molecule drug delivery carriers and analyze the advantages and limitations of the various loading strategies for small-molecule drugs. We also introduce drug release mechanisms and their application for the targeted treatment of various human diseases. In particular, this perspective describes how the corresponding drug-loading strategies should be selected based on the inherent physicochemical properties of the small-molecule drugs and the specific biomedical application, in order to facilitate clinical translation.
Pei-Hong Tong, Xi-Le Hu, Kai-Cheng Yan et al.· Journal of the American Chem...· 0 citations
This review focuses on clinically relevant long‑acting injectable and implantable systems, including polymeric nanoparticles, microspheres, in situ forming depots, and implantable devices, with an emphasis on how polymer chemistry governs their performance.
Stimuli-responsive drug-delivery systems (SRDDS) have transformed precision medicine by enabling spatiotemporal control over therapeutic release, significantly reducing off-target toxicity while enhancing efficacy at the disease site. Naturally occurring polysaccharides, such as hyaluronic acid, chitosan, alginate, and dextran stand out as premier scaffolds for these “smart” nanoplatforms due to their inherent biocompatibility, biodegradability, and abundance of reactive sites for molecular engineering. This review explores the versatility of polysaccharide functionalization, detailing how the introduction of molecular “switches” allows these biopolymers to sense and respond to specific physiological triggers. We analyze the mechanisms behind acid–labile bonds for pH-triggered release, redox-sensitive bridges for intracellular delivery, and enzyme-cleavable sequences for bio-catalytic activation. By bridging the gap between molecular functionalization and clinical utility, these bio-responsive polysaccharide architectures enable integrated physiological monitoring and theranostic applications. This review highlights the impact of these advancements in overcoming biological barriers, providing a sophisticated blueprint for the next generation of nature-derived, “intelligent” biomaterials in cancer therapy.
Mesoporous silica nanoparticles (MSNs) have been recognized as efficient, all-around nanocarriers for cancer therapy. This review highlights recent improvements in MSN design, synthesis, functionalization, and biomedical applications, as reflected in their individual textural characteristics of high surface area, pore size (2–50 nm), and high density of silanol groups, which allow high drug loading, controlled release, and multifunctionality. Researchers use advanced synthetic methods (sol–gel/Stöber, templated surfactant self-assembly, hydrothermal/solvothermal) and structural variations (hollow, core–shell, large-pore MSNs) to achieve precise control over particle size, morphology, and pore structure, enabling loading of a range of cargos (from small chemotherapeutics to nucleic acids). Active targeting, appendage of on-demand release. Surface engineering methods are discussed: PEGylation, ligand conjugation (folate, peptides, antibodies, aptamers), and stimuli-responsive gatekeepers (pH, redox, enzyme, light). This review presents up-to-date methods for MSN-based combination therapies and theranostic systems with real-time imaging agent monitoring in preclinical models. Preclinical work has been done in breast and lung cancers, and metastatic cancer models demonstrate improved tumor accumulation, cellular uptake, and therapeutic efficacy compared to free drugs. However, biodistribution studies have shown that uptake occurs via the mononuclear phagocyte system organs (liver, spleen), with size- and surface-dependent profiles. Translational issues are discussed with reference to scale-up and batch reproducibility, regulatory barriers, long-term safety concerns, and immunogenicity. Researchers identify opportunities underway, such as biomimetic coatings, nanomotors, customized MSN formulations, and combinations with gene and immune therapies, which have the potential to bridge the bench-to-bedside gap. Strategies for drug encapsulation (physical adsorption, electrostatic binding, covalent grafting) and secrecy (passive diffusion, stimulus-gated opening of gates) are considered, as are success stories of high-loading formulations. Though these results are encouraging in preclinical studies, clinical translation has not been aggressively pursued. The repertoire of silica platforms in clinical studies is mostly dense, not mesoporous, indicating that careful chronic toxicity research, along with standard manufacturing and early regulatory discussions, is necessary to accelerate safe use in clinical trials. In conclusion, although MSNs have significant potential for precision oncology due to their modularity and many functionalities, to realize their clinical potential, manufacturing, safety, and regulatory challenges should be addressed through standardized characterization and collaborative work across disciplines that are urgent priorities.
Reticular chemistry has enabled the design of crystalline porous frameworks, including metal-organic frameworks (MOFs) and covalent organic frameworks (COFs), with exceptional structural precision and functionality. Among these, hydrogen‑bonded organic frameworks (HOFs) represent a uniquely biocompatible class, constructed through reversible hydrogen bonds that confer dynamic responsiveness, mild‑condition processability, and inherent metal‑free composition. Despite these advantages ideal for biomedical use, HOFs remain underexplored in medicine compared to their coordination and covalent counterparts. This review systematically charts the emergence of HOFs as a versatile platform for biomedical applications. We first outline he design principles, synthetic strategies, and key parameters that govern the biomedical applications of HOFs. The core of the review focuses on the current state-of-the-art applications in biomarker detection, diagnostic imaging, advanced drug delivery, and therapeutic interventions. We discuss how the reversible and stimuli-responsive characteristics of HOFs enable intelligent functions and applications, such as multi-functional integration, triggered drug release and combination therapies. Finally, this review identifies the remaining challenges facing the field, while offering forward-looking perspectives on the clinical translation and future innovations of HOF-based nanomedicines. STATEMENT OF SIGNIFICANCE: Hydrogen-bonded organic frameworks (HOFs) are an emerging class of crystalline porous materials that combine metal-free composition, intrinsic biocompatibility, structural tunability, and stimuli-responsive hydrogen-bonded networks. Despite their rapid development in gas storage, separation, and catalysis, their biomedical potential remains largely unexplored. In this review, we summarize recent progress in the design and synthesis of HOFs and their applications in disease diagnosis, drug delivery, and therapeutic interventions. We further discuss the underlying mechanisms governing their biomedical functions and highlight key challenges that limit their translational development. Finally, we outline future research directions toward advancing HOFs for biomedical applications at the interface of supramolecular chemistry, materials science, and nanomedicine.
Pengyu Li, Yujie Zhang, Jie Wu et al.· Acta Biomaterialia· 0 citations
The development of efficient and targeted drug delivery systems remains a significant challenge, particularly for active pharmaceutical ingredients with poor aqueous solubility. Among various nanocarrier systems, Mesoporous Silica Nanoparticles (MSNs) have emerged as promising candidates due to their high surface area, tunable pore size (2-50 nm), thermal stability, and chemical modifiability. This review comprehensively discusses the rationale behind the utilization of MSN as drug delivery systems, focusing on how the type and concentration of surfactants, along with surface functionalization strategies, influence their physicochemical characteristics and pharmacokinetic performance. The synthesis of MSNs typically involves sol-gel processes using silica precursors (e.g., tetraethyl orthosilicate) and surfactants (e.g., cetyl trimethyl ammonium bromide, Pluronic F127), which dictate the morphology, particle size, and pore architecture of the resulting nanoparticles. Furthermore, surface modifications employing functional groups such as polyethylene glycol or pH-responsive polymers enhance biocompatibility, prolong systemic circulation, and enable controlled and site-specific drug release. Evidence from recent studies demonstrates that MSNs significantly improve drug loading efficiency, enhance solubility and bioavailability, and reduce off-target toxicity. Consequently, MSNs represent a highly versatile and modifiable platform with considerable potential for addressing the limitations of conventional drug delivery systems, particularly in oncology and the treatment of chronic diseases.
Ahmad Ainurofiq, Y. Ramadhana, Salma Aqilah Rachmadani et al.· Recent Advances in Drug Deli...· 0 citations