Lee, Soo-Hwan Cho, Yunkyeong Bang, Seunghwan Sung, Daeun Koo, Jahyun Kim, Seoyoung Koh, Youngil Kim, Hojun Lee, Hyojin 2025-08-26T02:00:40Z 2025-08-26T02:00:40Z 2025-08-20 2025-11 https://pubs.kist.re.kr/handle/201004/153030 Non-apoptotic cell death have emerged as promising strategies to overcome apoptotic resistance in cancer therapy. We suggest a hybrid gene delivery platform integrating adeno-associated virus (AAV)-mediated expression of receptor-interacting kinase 3(RIPK3) with manganese dioxide-polyethyleneimine (MnO2-PEI) to induce necroptosis and immunogenic cell death (ICD), thereby remodeling the tumor microenvironment and enhancing antitumor immunity. This platform combines high transduction efficiency with the tumor-accumulation ability and immunostimulatory potential of non-viral carriers. The MnO2-PEI nanosheets shields AAV from immune and hepatic clearance, thus enhancing tumor accumulation. This addresses a key limitation of naked AAV delivery. Simultaneously, the AAV payload offsets non-viral systems' low gene delivery efficiency. The platform induces robust damage-associated molecular patterns (DAMP) and tumor antigen release, thereby promoting dendritic cell maturation and cytotoxic T cell infiltration. Furthermore, Mn-2(+)-induced reactive oxygen species (ROS) amplify ferroptosis and, in conjunction with RIPK3-mediated necroptosis, remodel the immunosuppressive tumor microenvironment by promoting M1 macrophage polarization and a Th1-type immune response. In tumor re-challenge models, AAV/MnO2-PEI-treated mice exhibited durable antitumor immunity, thereby highlighting the potential of platform to establish long-term immune memory. This hybrid delivery system provides a potent strategy for synergistic cancer immunotherapy, effectively overcoming the limitations of both viral and non-viral vectors. English Wiley-VCH Verlag Nanoshield-Assisted Viral Gene Therapy with Induction of Non-Apoptotic Cell Death and Durable Antitumor Immunity Article 10.1002/advs.202507550 1 Advanced Science, v.12, no.41 Advanced Science 12 41 Y scie scopus 001542983500001 2-s2.0-105012628866 Chemistry, Multidisciplinary Nanoscience & Nanotechnology Materials Science, Multidisciplinary Chemistry Science & Technology - Other Topics Materials Science Article; Early Access ADENOASSOCIATED VIRUS SURVIVIN PROMOTER AAV VECTOR cancer immune therapy manganese-nanoshield necroptosis receptor-interacting kinase 3 (RIPK3) adeno-associated virus (AAV)