Abstract

Cancer stem cells (CSCs) and circulating tumor cells (CTCs) are pivotal contributors to tumor progression, metastasis, and therapeutic resistance. However, their effective eradication remains a significant hurdle in cancer treatments. Here, we report a mechanically optimized drug delivery platform based on ginsenoside Rh2-engineered tumor cell-derived microparticles (MP) loaded with doxorubicin (D@RM) for targeted elimination of CSCs and CTCs. Rh2 incorporation into MP modulates membrane lipid composition and disrupts lipid raft integrity, significantly reducing particle stiffness and enhancing deformability. These biomechanical changes promote tumor accumulation, deep tissue penetration, and clathrin-mediated uptake by CSCs. Concurrently, Rh2 suppresses drug efflux and stemness pathways, synergistically enhancing doxorubicin cytotoxicity toward CSCs. Moreover, D@RM efficiently bind and neutralize CTCs in circulation, thereby inhibiting metastatic dissemination. This study presents a versatile and translational strategy that integrates membrane mechanics and pharmacological modulation to improve the precision and efficacy of nanomedicine in cancer therapy.