Functionalized metal-organic frameworks as smart nanoplatforms: advancing tumor precision therapy through post-synthetic surface tailoring, challenges, and prospects for clinical translation.

Metal-organic frameworks (MOFs) have garnered significant attention as versatile nanocarriers for oncological drug delivery, owing to their exceptional porosity, structural tunability, extensive specific surface areas, and favorable drug loading and release kinetics, which collectively enable targeted payload delivery and reduced systemic toxicity. Nevertheless, the clinical promise of unmodified MOFs is severely curtailed by substantial in vivo biological barriers-including rapid bio-clearance, the immunosuppressive and acidic tumor microenvironment (TME), and inefficient cellular internalization-challenges that are ubiquitous across nanomedicine platforms and critically undermine therapeutic outcomes. This review provides a comprehensive examination of post-synthetic modification (PSM) as an indispensable strategy to surmount these obstacles. It systematically categorizes the diverse array of surface modifiers reported to date into natural polymers, synthetic polymers, nonpolymeric small molecules, inorganic materials, and multifunctional hybrid architectures, while elucidating how each class can enhance biocompatibility, colloidal stability, circulation half-life, active targeting, and stimuli-responsive cargo release. Crucially, the review critically appraises the intrinsic trade-offs introduced by surface engineering, including increased hydrodynamic diameter, impaired tumor penetration, heightened synthetic and characterization complexity, and unpredictable perturbations to biodegradation pathways and immune system interactions. Despite robust preclinical validation, the translational trajectory of surface-engineered MOF-based therapeutics remains encumbered by formidable challenges spanning scalable and reproducible manufacturing, long-term biosafety assessment, and stringent regulatory approval. By delineating current advances, critical limitations, and prospective directions, this review highlights the delicate equilibrium between surface functionalization and biological performance that must be achieved to realize the clinical potential of PSM-optimized MOF nanomedicines.