Lipid-conjugated siRNA hitchhikes endogenous albumin for tumor immunotherapy

Abstract

With the development of a small interfering RNA (siRNA) delivery strategy, increasing siRNA therapeutics for tumor treatment appeared in clinical trials and pre-clinical development. However, the test results of such therapeutics unveiled that efficient siRNA delivery to tumor tissues is still challenging. Albumin is considered an ideal carrier for delivering hydrophobic agents into tumor tissue because it is highly concentrated and long-circulating in blood and has propensity of tumor enrichment. Herein, we synthesized lipid conjugated siRNAs (LsiRNAs), which showed high affinity to albumin. Mechanistically, LsiRNAs non-covalently bind to the hydrophobic core of albumin through its octadecyl tails. The small size of albumin/LsiRNAs allows the complex to penetrate tumor tissue efficiently. Biodistribution test proved that albumin extremely prolonged circulation time and increased tumor retention of associated LsiRNAs. Notably, LsiRNA against programmed death ligand-1 (Pdl1) efficiently suppressed tumor growth as well as prolonged survival time of tumor bearing mice by increasing infiltration of CD8+ T cells as well as promoted the maturation of dendritic cells both in tumor and lymph. Together, LsiRNAs provide a simple but effective way for siRNA tumor delivery that “hitchhikes” on albumin.