Scheme 1.

Synergistic activity of SMAC and DOX by Aposomes to potentiate ICB therapy. a Cancer cell-specific and pro-apoptotic prodrug of SMAC-P-FRRG-DOX, constructed with cathepsin B-cleavable SMAC-P (AVPIAQFRRG) and DOX, is formulated as clinically-relevant PEGylated liposomes, resulting in Aposomes. b In colon tumor bearing mice, Aposomes efficiently accumulate within the targeted tumor tissues via nanoparticle-derived EPR effect. c Prodrug of SMAC-P-FRRG-DOX is released from Aposomes and cleaved to SMAC-P and DOX by cathepsin B overexpressed in cancer cells. d The synergistic activity of SMAC-P and DOX induces a potent ICD accompanying DAMP expressions in cancer cells, resulting in DC maturation and T cell recruitment and activation and eventually eradicating the tumors. e Meanwhile, SMAC-P-FRRG-DOX released from Aposomes maintains the non-toxic inactive state in the normal tissues owing to lower cathepsin B, reducing the risk of complications. In same context, Aposomes also prevent the immunosuppression by systemic chemotherapy owing to minimized non-specific cytotoxicity to T cells, DCs and macrophages, which express a significantly low cathepsin B compared to cancer cells