Programmable double-unlock nanocomplex self-supplies phenylalanine ammonia-lyase for precise phenylalanine deprivation of tumors

Essential amino acids(EAAs)deprivation is a potential antitumor approach because EAAs are critical for tumor growth.To efficiently inhibit tumor growth,continuous deprivation of EAAs is required,how-ever,continuous deprivation without precise control will introduce toxicity to normal cells.Herein,a programmable double-unlock nanocomplex(ROCK)was prepared,which could self-supply phenylalanine ammonia-lyase(PAL)to tumor cells for phenylalanine(Phe)deprivation.ROCK was double-locked in physiological conditions when administered systemically.While ROCK actively targeted to tumor cells by integrinαvβ3/5 and CD44,ROCK was firstly unlocked by cleavage of protease on tumor cell membrane,exposing CendR and R8 to enhance endocytosis.Then,hyaluronic acid was digested by hyaluronidase overexpressed in endo/lysosome of tumor cells,in which ROCK was secondly unlocked,resulting in pro-moting endo/lysosome escape and PAL plasmid(pPAL)release.Released pPAL could sustainably express PAL in host tumor cells until the self-supplied PAL precisely and successfully deprived Phe,thereby block-ing the protein synthesis and killing tumor cells specifically.Overall,our precise Phe deprivation strategy effectively inhibited tumor growth with no observable toxicity to normal cells,providing new insights to efficiently remove intratumoral nutrition for cancer therapy.

Reversing cancer immunoediting phases with a tumor-activated and optically reinforced immunoscaffold

In situ vaccine(ISV)is a promising immunotherapeutic tactic due to its complete tumoral antigenic repertoire.However,its efficiency is limited by extrinsic inevitable immunosuppression and intrinsic immunogenicity scarcity.To break this plight,a tumor-activated and optically reinforced immunoscaffold(TURN)is exploited to trigger cancer immunoediting phases regression,thus levering potent systemic antitumor immune responses.Upon response to tumoral reactive oxygen species,TURN will first release RGX-104 to attenuate excessive immunosuppressive cells and cytokines,and thus immunosuppression falls and immunogenicity rises.Subsequently,intermittent laser irradiation-activated photothermal agents(PL)trigger abundant tumor antigens exposure,which causes immunogenicity springs and preliminary infiltration of T cells.Finally,CD137 agonists from TURN further promotes the proliferation,function,and survival of T cells for durable antitumor effects.Therefore,cancer immunoediting phases reverse and systemic antitumor immune responses occur.TURN achieves over 90%tumor growth inhibition in both primary and secondary tumor lesions,induces potent systemic immune responses,and triggers superior long-term immune memory in vivo.Taken together,TURN provides a prospective sight for ISV from the perspective of immunoediting phases.