Tumor-Specific Delivery of Nanomedicines via a Nutrient Sensing-Driven Pathway Mediated by Niemann-Pick C1-Like 1

At the cellular level, exogenous nanoparticles (NPs) usually demonstrate an uncoupling between membrane binding and internalization processes, and the major lysosomal trapping pathway leads to a hampered delivery efficiency. Achieving active cellular uptake of NPs and nonlysosomal intracellular trafficking concurrently has remained a considerable challenge. Here, we develop a tumor-specific delivery strategy by exploiting the Niemann-Pick C1-Like 1 (NPC1L1)-mediated nutrient sensing pathway. As a transmembrane protein for intestinal and hepatic cholesterol transport, NPC1L1 is ectopically overexpressed in various types of tumors including lung and liver carcinoma. Hence, we designed cholesterol surface-displayed NPs (CSD-NPs) that exhibit selective and rapid internalization into tumor cells through the nonlysosomal pathway, facilitated by NPC1L1-mediated nutrient sensing and signaling of surface-displayed cholesterol. After the underlying molecular mechanism was clarified, the CSD strategy was utilized to reconstruct the commercial anticancer Doxil nanoformulation and fabricate tumor-specific gene delivery nanovehicles. CSD-NPs exhibited enhanced antitumor activity at low doses with an inhibition rate of approximately 90% for both chemotherapy and gene therapy and substantially extended survival. In conclusion, the reported cholesterol surface-display strategy offers a promising platform for developing nanomedicines with advanced therapeutic functions.