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, Mn²⁺-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.

Adv Sci (Weinh). 2025 Aug 4:e07550.

https://advanced.onlinelibrary.wiley.com/doi/10.1002/advs.202507550https://advanced.onlinelibrary.wiley.com/doi/10.1002/advs.202507550