A Biomimetic Micro‐Nano System Maximizing ‘Active Transport and Retention’ Effect in Solid Tumors

ABSTRACT The Active Transport and Retention (ATR) principle offers a new strategy to enhance tumor entry of nanodrugs via transcytosis. However, its application is limited by poor tumor‐homing, endothelial polarized efflux, and uncontrollable transcytosis of the nanodrug. Herein, we construct a bio‐mimetic micro‐nano system (PG@BAM‐L _RC ) comprising nanoliposomes (L _RC ) and berbamine (BAM) within platelet‐derived microcarrier (PG), leveraging PG's tumor‐homing ability and MMP‐9 responsive remodeling for tumor‐specific cargo release. Thereafter, BAM selectively promotes basal transendothelial transport of L _RC toward the tumor by modulating apical recycling endosomes. While R8 promotes the cellular uptake, the arginine‐lysine‐lysine‐arginine‐cysteine (Cys) ligand facilitates Golgi‐targeted transendothelial transport of L _RC, bypassing the endo‐lysosome pathway. Once inside tumor cells, furin‐mediated Cys‐cleavage halts transcytosis, yielding superior intracellular drug retention compared to the non‐cleavable Cys counterpart (L _RC’ ). Four murine tumor models are established, demonstrating high heterogeneity in collagen density, vascularity, and EPR effects. An orthotopic pancreatic tumor, characterized by minimal EPR effect, is selected to demonstrate the ATR effect of PG@BAM‐L _RC . PG@BAM‐L _RC loaded with BAY‐872243 exhibits exceptional tumor accumulation and therapeutic outcome compared to L _RC, PG@L _RC without BAM, and PG@BAM‐L _RC . Collectively, this study establishes PG@BAM‐L _RC as a robust tumor‐targeting system leveraging the ATR mechanism while addressing tumor heterogeneity.