Kim, Jinseong Shim, Man Kyu Moon, Yujeong Kim, Jeongrae Cho, Hanhee Yun, Wan Su Shim, Nayeon Seong, Joon-Kyung Lee, Yonghyun Lim, Dong-Kwon Kim, Kwangmeyung 2024-03-18T01:30:16Z 2024-03-18T01:30:16Z 2024-03-14 2024-03 1477-3155 https://pubs.kist.re.kr/handle/201004/149488 Background Immunogenic cell death (ICD) is a crucial approach to turn immunosuppressive tumor microenvironment (ITM) into immune-responsive milieu and improve the response rate of immune checkpoint blockade (ICB) therapy. However, cancer cells show resistance to ICD-inducing chemotherapeutic drugs, and non-specific toxicity of those drugs against immune cells reduce the immunotherapy efficiency. Methods Herein, we propose cancer cell-specific and pro-apoptotic liposomes (Aposomes) encapsulating second mitochondria-derived activator of caspases mimetic peptide (SMAC-P)-doxorubicin (DOX) conjugated prodrug to potentiate combinational ICB therapy with ICD. The SMAC-P (AVPIAQ) with cathepsin B-cleavable peptide (FRRG) was directly conjugated to DOX, and the resulting SMAC-P-FRRG-DOX prodrug was encapsulated into PEGylated liposomes. Results The SMAC-P-FRRG-DOX encapsulated PEGylated liposomes (Aposomes) form a stable nanostructure with an average diameter of 109.1？±？5.14 nm and promote the apoptotic cell death mainly in cathepsin B-overexpressed cancer cells. Therefore, Aposomes induce a potent ICD in targeted cancer cells in synergy of SMAC-P with DOX in cultured cells. In colon tumor models, Aposomes efficiently accumulate in targeted tumor tissues via enhanced permeability and retention (EPR) effect and release the encapsulated prodrug of SMAC-P-FRRG-DOX, which is subsequently cleaved to SMAC-P and DOX in cancer cells. Importantly, the synergistic activity of inhibitors of apoptosis proteins (IAPs)-inhibitory SMAC-P sensitizing the effects of DOX induces a potent ICD in the cancer cells to promote dendritic cell (DC) maturation and stimulate T cell proliferation and activation, turning ITM into immune-responsive milieu. Conclusions Eventually, the combination of Aposomes with anti-PD-L1 antibody results in a high rate of complete tumor regression (CR: 80%) and also prevent the tumor recurrence by immunological memory established during treatments. English BioMed Central Cancer cell-specific and pro-apoptotic SMAC peptide-doxorubicin conjugated prodrug encapsulated aposomes for synergistic cancer immunotherapy Article 10.1186/s12951-024-02314-w 1 Journal of Nanobiotechnology, v.22, no.1 Journal of Nanobiotechnology 22 1 Y scie scopus 001184965900001 Biotechnology & Applied Microbiology Nanoscience & Nanotechnology Biotechnology & Applied Microbiology Science & Technology - Other Topics Article Aposomes Cancer immunotherapy Immune checkpoint blockade PEGylated liposome Immunogenic cell death Drug resistance