Holistic and Multivalent Engineering of In Vivo Nanomedicine Reactions for Enhanced Multistage Tumor Delivery.

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.