Why Your Nanomedicine Might Not Be as Precise as It Claims: A New Framework Demands Proof

For decades, the promise of precision drug delivery has rested on a seductive idea: build a nanoparticle small enough to navigate the bloodstream, coat it with a molecule that recognizes diseased cells, and let it release its therapeutic cargo exactly where and when it is needed. Metal-organic frameworks (MOFs) and covalent organic frameworks (COFs) have emerged as two of the most versatile material platforms for realizing this vision. Both are reticular materials—extended crystalline networks assembled from molecularly defined building blocks—that offer ordered pores, high surface areas, and a density of addressable chemical sites unmatched by most conventional carriers. Yet a new review published in Frontiers in Drug Delivery argues that the field has been conflating impressive materials science with genuine precision medicine, and it proposes a rigorous evidence framework to close that gap.

The review, led by Xinwei Li, Haonan Zhang, Ruidong Ding, and Feng Wang at the Affiliated Hospital of Qingdao University and the University of Chinese Academy of Sciences, systematically dissects what the term “precision” should actually mean when applied to framework-based nanomedicine. Drawing on approximately 1,200 records identified through PubMed, Web of Science, Scopus, and Crossref, from which roughly 150 primary studies and reviews were retained, the authors construct a five-dimensional definition of precision delivery: material, spatial, temporal, mechanistic, and translational. Each dimension carries a distinct evidentiary burden, and failure at any single stage can erase an advantage established at another.

The distinction matters because the biological reality of drug delivery is unforgiving. Landmark analyses have shown that only a median of roughly 0.7 percent of an injected nanoparticle dose reaches solid tumors, and that delivery efficiency is governed more by biological barriers—dilution, protein adsorption, immune clearance, vascular endothelium, and the mononuclear phagocyte system—than by material performance in buffered solution. A particle may load a drug efficiently yet release it prematurely in plasma. It may accumulate in a tumor while remaining trapped inside stromal phagocytes. It may enter target cells without ever releasing functional macromolecular cargo. These failure modes are invisible to the metrics most commonly reported in the literature.

MOFs and COFs approach the problem from complementary directions. MOFs are built from metal ions or clusters connected by multidentate organic linkers, and their coordination chemistry offers a tunable balance between stability and degradability. Zirconium frameworks such as UiO-66, with their strong Zr(IV)–carboxylate bonds, resist hydrolysis; zinc-based ZIF-8 remains stable near physiological pH but dissolves once imidazolate linkers are protonated in acidic endosomal compartments; iron-carboxylate MIL frameworks are designed for biodegradation; and cyclodextrin MOFs coordinate potassium with γ-cyclodextrin to form bioabsorbable carriers. COFs, by contrast, are constructed entirely from organic building blocks joined by covalent linkages, offering metal-free or metal-sparse backbones, conjugated pore walls capable of light harvesting, and a stability hierarchy that runs from labile boronate esters through imines and hydrazones to robust β-ketoenamine, imide, and sp²-carbon linkages.

Neither family is intrinsically more precise. The review argues that precision emerges only from matching the framework to the cargo, the route of administration, the biological barrier, and the intended pharmacology. MOFs may be favored when coordination chemistry, metal-center catalysis, or metal-associated imaging is essential. COFs may be favored when a metal-free pore environment, covalently encoded trigger chemistry, or tunable aromatic interactions is the decisive function. Hybrids—MOF-on-MOF, MOF@COF, COF@MOF, or membrane- and vesicle-coated composites—are justified only when the interface creates a measurable gain that a single framework or simpler carrier cannot provide.

The cargo itself introduces further complexity. Small molecules can enter framework pores and interact through hydrophobic forces, hydrogen bonding, electrostatics, π-stacking, or coordination, but high loading is not the design endpoint; the goal is an affinity window that suppresses leakage during transit while permitting pharmacologically useful release at the target site. Proteins, enzymes, and nucleic acids pose a separate challenge because their dimensions, conformational integrity, and functional compartment matter. Biomimetic mineralization—growing a MOF shell around a macromolecule—can protect cargo under mild aqueous conditions, but high encapsulation efficiency does not guarantee retained activity, and fluorescent uptake does not establish cytosolic release. Therapeutic gases such as nitric oxide, carbon monoxide, and hydrogen sulfide require local concentration–time control because their effects are highly dose- and context-dependent, and gas adsorption measured under high pressure is not equivalent to a useful dose in hydrated tissue.

Spatial precision demands more than a targeting ligand. The review emphasizes that whole-organ fluorescence supports organ-associated signal, not intact-particle delivery to a specific cell type. Cell uptake does not establish cytosolic release, and intracellular localization does not establish functional protein, RNA, or enzyme activity. A convincing targeting study should report blood exposure, whole-organ distribution, tumor concentration, cell-type distribution within the tumor, and competition or receptor-loss controls. Active ligands typically improve cellular binding and internalization more reliably than they increase the fraction of injected dose reaching a tumor, and changes in formulation can alter pharmacokinetics independently of receptor recognition.

Temporal precision is equally demanding. Acid-triggered disassembly is the most common release mechanism, but many studies compare pH 7.4 with pH 5.0 in salt-poor buffers, whereas extracellular tumor pH is typically only moderately acidic (about 6.5–6.8) and protein-rich, while endosomal and lysosomal compartments reach roughly pH 4.5–5.5 only after cellular uptake. Redox-responsive systems exploit elevated intracellular glutathione or disease-associated reactive oxygen species, but the biological matrix introduces confounders: millimolar glutathione scavenges ROS generated by oxidase- and peroxidase-like nanozymes, protein coronas can physically block catalytic sites, and physiological ionic strength alters metal coordination. Externally applied energy—light, ultrasound, magnetic fields—provides spatial focusing, but strong effects in superficial xenografts do not necessarily translate to deep or disseminated disease, and the energy field and carrier distribution must overlap at the required scale.

The translational dimension is where the field faces its steepest climb. As of the literature search date, no MOF- or COF-based drug product has received marketing approval, although early clinical translation has begun with hafnium-based nanoscale MOF radiosensitizers. RiMO-301 completed a Phase 1 dose-escalation trial combining intratumoral injection with palliative radiation in advanced tumors, and is now being evaluated in a Phase 1b/2a trial for head-and-neck cancer. A related candidate, RiMO-401, entered a Phase 1 trial but was terminated owing to slow enrolment. For most framework candidates, safety discussions still rest on preclinical evidence, and the review stresses that a short viability assay establishes only an initial concentration range. A development-oriented package should include haemocompatibility, complement and cytokine responses, immunogenicity, genotoxicity, repeat-dose exposure, and organ-specific endpoints determined by actual biodistribution.

Manufacturing adds another layer of difficulty. Many MOFs and COFs are prepared in dilute solvothermal batches using high-boiling organic solvents, and particle size, defect density, and residual solvent can drift between batches when mixing, heating, and cooling rates are not tightly controlled. Continuous-flow synthesis offers tighter residence-time and temperature control, while green or aqueous solvent systems reduce the downstream purification burden. Activation and drying are not trivial steps: the porosity that underpins loading capacity depends sensitively on solvent exchange and thermal or supercritical treatment, and incomplete activation leaves residual solvent in the pores that reduces usable capacity. Sterilization and storage are often deferred until late development, yet filtration may be impossible for larger particles, and heat, irradiation, or chemical sterilants can change frameworks, linkers, drugs, and biological coatings in unpredictable ways.

The review’s most consequential contribution is its claim-to-evidence mapping, which converts “precision” from an aspirational label into a set of testable criteria. A targeted delivery claim requires quantitative target-cell exposure at the stated resolution, not organ fluorescence. A functional macromolecule delivery claim requires sequence-, activity-, or rescue-based endpoints, not fluorescent uptake. A biodegradable carrier claim requires identification and time-resolved disappearance of the intact framework plus the fate of its fragments, not merely loss of crystallinity in buffer. A synergistic therapy claim requires dose- or exposure-matched interaction analysis, not simply a combination that outperforms either component alone. A theranostic claim requires that the diagnostic output inform localization, activation, response, or dosing, not merely that the particle happen to be fluorescent.

The authors also confront the field’s tendency toward conceptual overreach. A large Brunauer–Emmett–Teller surface area measured on an activated powder does not directly predict usable loading in a hydrated nanosuspension. The word “biocompatible” is frequently assigned after short-term viability or histology experiments, even though framework degradation can generate metal ions, ligands, fragments, and re-coordinated species with distinct kinetics and toxicological profiles. Nutritional familiarity with a free element cannot establish the safety of the corresponding framework. A precision claim must therefore be evaluated at the level of the complete product and its transformation over time, not inferred from the reputation of an individual building block.

Beyond conventional tumor models, the review highlights metabolic and fibrotic diseases as more stringent tests of precision. These conditions involve diffuse tissue, chronic dosing, multiple cell populations, and disease-dependent changes in receptor expression, redox state, and extracellular matrix. The authors’ own preclinical program illustrates the approach: a MOF-818-based nanozyme modified with an ASGR1 antibody and loaded with uridine diphosphate glucose coordinated antioxidant catalysis, lipid efflux, and suppression of lipogenesis in models of metabolic dysfunction-associated steatotic liver disease. A related anti-ASGR1 nanocomplex combined a MIL-family core with thyroid hormone for rapid reduction of donor-liver steatosis, including evaluation in transplantation-associated perfusion. A MOF-engineered exosome system encapsulated exosomes with copper-cysteine nanozyme activity in a ZIF-containing architecture and reported preclinical benefit across lung, liver, and kidney fibrosis models. These remain preclinical findings, and the authors are explicit that they do not demonstrate human pharmacokinetics, transplant benefit, or chronic safety.

Local delivery offers a practical translation route for complex frameworks because it limits systemic exposure and permits high concentrations at an accessible site. Wound dressings, injectable gels, coatings, and microneedles can retain MOFs or COFs while allowing drugs, ions, or catalytic products to diffuse. A bimetallic MOF nanozyme composite for diabetic wound management combined wearable glucose sensing with microenvironment-dependent catalytic treatment, illustrating a closed-loop concept in which a disease biomarker is measured and the same material family contributes to therapy. The authors caution, however, that a true closed loop would require the sensor output to alter dose or activation in real time; parallel sensing and treatment is an important step but not yet autonomous feedback control.

The review closes with a set of design rules that prioritize simplicity and accountability over architectural ambition. Begin with a delivery bottleneck, not a framework. Define the active entity and its dose. Couple cargo affinity to the intended release pathway. Measure precision at the claimed spatial scale. Treat the biological interface as a dynamic component. Separate trigger response from framework degradation. Build safety and manufacturability into candidate selection. Publish negative results. Test precision against a simpler benchmark. A framework that achieves similar efficacy with a lower dose, wider safety margin, uniquely protected cargo, or controllable activation has a defensible value proposition; a framework that only increases loading relative to an unoptimized comparator does not. Under this discipline, MOFs and COFs can evolve from impressive porous materials into accountable drug products whose chemical programmability is matched by pharmacological and manufacturing precision.

Subject of Research: Precision drug delivery using metal-organic and covalent organic frameworks

Article Title: Metal-organic and covalent organic frameworks for precision drug delivery: a precision-by-design evidence framework for biologically accountable nanomedicine

Article References: Li, X., Zhang, H., Ding, R., & Wang, F. (2026). Metal-organic and covalent organic frameworks for precision drug delivery: a precision-by-design evidence framework for biologically accountable nanomedicine. Frontiers in Drug Delivery, 6, Article 1970554. https://doi.org/10.3389/fddev.2026.1970554

Image Credits: AI Generated

DOI: 10.3389/fddev.2026.1970554

Keywords: metal-organic frameworks, covalent organic frameworks, precision drug delivery, nanomedicine, stimuli-responsive release, nanozymes, theranostics, biomimetic coatings, biodegradable carriers, drug delivery barriers, quality by design, translational nanomedicine