A Decade-Long Journey in Design Strategies and Structure-Property Relationships of Covalent Organic Framework...

Over the past decade, covalent organic frameworks (COFs) have emerged as promising chemotherapeutic drug-delivery nanocarriers (DDNs) owing to their precise pore channels combined with tunable framework chemistry. Unlike non-porous analogues, this synergy has led to remarkable drug-loading capacities (up to 70-90 wt%), stimuli-responsive drug-release profiles, and exceptionally high biocompatibility (up to 800 µg mL^-1). To date, efforts have largely been made to optimize COF porosity, linkage chemistry, and surface functionality. Yet critical parameters regulating in vivo chemotherapeutic performance of COF-DDNs, namely, immune response, sub-100 nm particle size control, long-term colloidal stability and blood circulation half-life, along with precise clearance pathways, remain underexplored. Building on these, this review article identifies links between the structural features of COFs and chemotherapeutic drug-delivery metrics, including drug-loading efficiency, release kinetics, biocompatibility, cytotoxicity, targeting specificity, cellular uptake, internalization mechanisms, biodegradability, and nanocarrier clearance pathways. Through quantitative analyses of these interdependent design parameters and therapeutic delivery standards, a data-driven roadmap is provided to accelerate the translation of COF-DDNs into clinical chemotherapy. Thus, this article charts a clear path toward next-generation COF-based chemotherapeutic DDNs, setting the stage to transform global cancer solutions.