Bacterial outer membrane vesicle-based biomimetic nitric oxide-releasing nanogenerator for boosting antitumor efficiency of enzyme dynamic therapy via augmented autophagy and immunoactivation

Recently, enzyme dynamic therapy (EDT) has attracted great attention in cancer therapy. Nevertheless, the limited H 2 O 2 concentration in the tumor microenvironment (TME) and the induction of autophagy significantly impair the anticancer efficacy of EDT. Herein, a bacterial outer membrane vesicles (OMVs)-based nitric oxide (NO)-releasing nanogenerator was synthesized to enhance the anticancer efficacy of EDT. Specifically, hollow polydopamine nanospheres (HPDA) were first prepared and used as a carrier to load lactate oxidase (LOX), the NO-releasing donor BNN6 and chloroperoxidase (CPO), followed by surface coating with OMVs to obtain the biomimetic nanogenerator HPDA@LBC@OMV. Due to the excellent tumor-targeting ability of OMVs, HPDA@LBC@OMV displayed highly efficient accumulation in 4T1 tumor tissues. In the TME, HPDA@LBC@OMV firstly catalyzed lactic acid to produce a substantial amount of H 2 O 2 , which subsequently triggered the simultaneous generation of NO and singlet oxygen ( 1 O 2 ) through cascade catalytic reactions, ultimately resulting in significant inhibition of 4T1 tumors. Mechanistic studies revealed that the synergistic NO/ 1 O 2 anticancer effect inhibited 4T1 tumors by inducing excessive autophagy. More importantly, it was demonstrated that the synergistic effect-induced excessive autophagy effectively triggered immunogenic cell death (ICD) in dying tumor cells, thereby further activating the body’s immune response by converting “cold” tumors into “hot” tumors to enhance anticancer immunotherapy.