Albumin-bound alkylated resiquimod for enhanced cancer immunotherapy.

Nanoparticle albumin-bound technology is a highly successful drug delivery platform, exemplified by the development of nab-paclitaxel. However, its application in the state-of-the-art cancer immunotherapy remains relatively underexplored, partly due to the weak binding affinity of many immune agonists to albumin. In this study, a hydrophobic long-chain alkylation strategy was employed to synthesize pentadecanol-modified resiquimod (C15-R848) to enable the formation of stable albumin-bound nanoagonist (CR@BSA) for enhanced cancer immunotherapy. CR@BSA effectively repolarized macrophages from tumor-supportive M2 to antitumor M1 phenotype and promoted the secretion of pro-inflammatory cytokines. In MC38 tumor-bearing mice, systemically administered CR@BSA accumulated in tumors and elicited a robust systemic antitumor immune response by reprogramming macrophages, activating dendritic cells (DCs), and enhancing intratumoral CD8+ T cells infiltration. When combined with anti-programmed death-1 antibody (αPD-1), CR@BSA significantly suppresses tumor metastasis and induces complete tumor regression in 37.5% of treated mice bearing orthotopic 4T1 breast tumors. This study provides a simple but effective strategy for the development of albumin-bound nanomedicine to improve cancer immunotherapy.