In-situ self-assembled vaccine constructed with dual switchable nanotransformer for tumor immunotherapy

Abstract

The development of tumor autologous vaccines has achieved excellent progress in recent years. Here, a dual switchable nanotransformer (NLM/DMG) is prepared to construct an in-situ self-assembled vaccine (ISV). NLM/DMG is constructed with doxorubicin (DOX), 1-methyl-d-tryptophan (1MT)-coloaded liposome (LCL/DM) and immunoadjuvant (cGAMP)-loaded vaccine precursor (MCL/G) modified with maleimide (Mal) enveloped by negatively charged CMCS-PEG-NGR. NLM/DMG target tumor tissue and realize a size-shrinkable (171.30 nm vs 43.15 nm) and charge-reversible (-24.30 mV vs 6.19 mV) dual switch to release LCL/DM and MCL/G for deep tumor penetration. LCL/DM target tumor cells and release DOX and 1MT. DOX induces an ICD effect to promote the release of antigens while reducing tumor burden. MCL/G is self-assembled into ISV through capturing antigens via Mal, thus promoting the maturation of DCs. 1MT inhibits the activity of indoleamine-2,3-dioxygenase, thereby reversing the tumor immunosuppressive microenvironment. The therapeutic evaluation demonstrates that NLM/DMG effectively inhibit primary tumor growth, rechallenge tumor growth, postoperative recurrence and metastasis. In short, NLM/DMG penetrates deep into tumors to realize true in-situ construction of vaccines, and it overcomes some deficiencies of existing autologous vaccines by intervening in-situ on antigen production, vaccine formation and T cell efficacy. NLM/DMG is a simple and general autologous vaccine in-situ construction system.