Size Modulation of Dendritic Dots Dictates CAPIR Cascade Efficiency for Enhanced Tumor Therapy

Abstract Efficient cancer nanotherapy hinges on the sequential execution of the CAPIR cascade (Circulation, Accumulation, Penetration, Internalization, Release), a conceptual framework that describes the multistep journey of nanocarriers from systemic administration to intracellular payload release. However, how nanoparticle size, especially within the ultrasmall size regime, regulates performance across the full CAPIR cascade remains poorly understood. Here, we engineered successive generations of acetylated perylenediimide (PDI)-cored polylysine dendritic dots (PDI–PLL-Ac) with precise size control (6.3–11.1 nm) and systematically evaluated their behavior across all five steps of the CAPIR cascade. Our results reveal distinct size-dependent delivery dynamics of the dendritic dots: the ∼11 nm G8-Ac achieved a more favorable balance among the tested dendritic dots, integrating prolonged blood circulation, efficient tumor accumulation involving both the enhanced permeability and retention (EPR) effect and transcytosis-enabled active extravasation and penetration (TAEP)-associated active transport, deep penetration into avascular tumor regions, effective cellular internalization, and enhanced therapeutic efficacy. When loaded with camptothecin (CPT), G8-CPT-Ac induced extensive apoptosis throughout the tumor parenchyma and exhibited superior antitumor efficacy in 4T1 models compared to smaller counterparts and CPT-11, a clinically used CPT prodrug. This work provides critical mechanistic insights into size-dependent nanocarrier performance across the CAPIR cascade and identifies G8-Ac (∼11 nm) as the most favorable candidate among the tested generations (G5-Ac to G8-Ac). These findings offer a rational strategy for designing high-efficiency, clinically translatable tumor-targeted theranostic nanomedicines enhanced tumor accumulation involving both the EPR effect and active transcellular transport contributions.