Surface-displayed cholesterol enhances penetration and anti-tumor activity of a platinum nanodrug by targeting NPC1L1-expressing cancer associated fibroblasts.

Transcytosis-mediated delivery effectively enhances tumor penetration of nanodrugs but is less efficacious in stroma-rich tumors. Cancer associated fibroblasts (CAF) can represent a physical barrier for drug delivery in tumor cells. Herein, by selectively targeting NPC1L1-cancer associated fibroblasts, surface-displayed cholesterol enhances the delivery of a platinum nanodrug (PtD-Chol) in stroma-rich tumors, restoring anti-tumor efficacy. The findings reveal that PtD-Chol, acting through the 'shared entry portal' of NPC1L1 triggers cross-multicellular transport (CMCT) within tumors, shuttling PtD-Chol across the CAF barrier via the endocytic recycling compartment-endoplasmic reticulum-Golgi pathway, thereby enabling deep penetration into tumor. This strategy restores nanodrug efficacy in CAF-rich refractory tumor models in female mice, and suppresses both primary growth and CAF-driven metastasis via tumor microenvironment remodeling. This proposed nanodrug delivery paradigm offers an approach to tackle the critical barriers of tumor penetration and therapeutic efficacy in nanomedicine.