A Flexibility-Driven Delivery Strategy for Cationic Liposomes to Enhance Tumor Penetration and Promote Membrane Fusion-Mediated Cellular Entry

Cationic liposomes have emerged as a promising delivery vehicle for chemotherapy. However, their strong electrostatic interaction with tumor vascular endothelium and stroma lead to predominant accumulation at the periphery, thereby restricting deep tumor penetration. Herein, we propose a mechanical programming strategy that modulates the flexibility of cationic liposomes to enhance their tissue permeability, delivery efficiency and antitumor efficacy. By incorporating sodium cholate as a flexibilizer, we engineered a cabazitaxel (CTX)-loaded cationic flexible liposome (CTX@CFL) with enhanced membrane fluidity and deformability. This flexibility-driven redesign shifted the cellular uptake mechanism from endocytosis to membrane fusion, facilitating direct cytosolic delivery and bypassing lysosomal degradation. Consequently, CTX@CFL demonstrated superior transendothelial transport, significantly deeper tumor penetration, and enhanced cytotoxicity compared to conventional cationic rigid liposomes. In vivo , CTX@CFL achieved markedly improved tumor accumulation, intratumoral distribution, and potent antitumor efficacy with favorable biocompatibility. This work establishes ‘flexibility modulation’ as a core design strategy that fundamentally overcomes the intrinsic delivery barriers of cationic liposomes. It provides a translatable engineering approach to unlock the full therapeutic potential of cationic liposomal systems in solid tumor therapy.