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

Abstract

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. Cancer associated fibroblasts can represent a physical barrier for drug delivery in tumor cells. Here the authors show that, by selectively targeting NPC1L1-cancer associated fibroblasts, surface-displayed cholesterol enhances the delivery of a platinum nanodrug in stroma-rich tumors, restoring anti-tumor efficacy.