Rundi Song, Jie Cen, Rong Cai, Chenzhi Yao, Qiangqiang Shi, Yuben Zhang, Chengzhou Song, J. F. Tan, Mingxuan Hou, Rong Li, Mengfan He, Jinming Hu, Chunying Chen, Shiyong Liu
Efficient delivery of nanomedicines to tumors is crucial for achieving on-demand therapeutic outcomes. However, this remains a formidable challenge due to the presence of multiple biological barriers, which significantly hinder clinical translation. Here, we present a "reactive accumulation, exofacial protein thiol capture, and targeting" (ReACT) strategy to holistically modulate nanomedicine transportation and overcome systemic, microenvironmental, and cellular barriers. Using m-tetrahydroxyphenylchlorin (mTHPC)-based nanomedicines functionalized with multivalent maleimide (MI), we demonstrate in situ albumin capture to form a protein corona that can evade immune clearance and extend circulation. At tumor sites, albumin can greatly enhance tumor delivery efficiency in orthotopic pancreatic cancer compared to succinimide (SI)-functionalized analogs. Residual MI moieties engage exofacial thiols to drive caveolae-mediated endocytosis, while intracellular disassembly triggered by cytoplasmic thiols facilitates drug release and transcytosis. This approach, extended to STING agonists, significantly improves therapeutic outcomes in pancreatic ductal adenocarcinoma and triple-negative breast cancer models, establishing ReACT as a versatile platform for overcoming delivery barriers in nanomedicine.