A Decade‐Long Journey in Design Strategies and Structure–Property Relationships of Covalent Organic Framework Nanocarriers for Anticancer Drug Delivery

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.