Programmable three‐state nanoreactor for spatiotemporally controlled tumor therapy

Abstract

Stimuli‐responsive nanomaterials hold great promise for precision cancer therapy; however, achieving spatiotemporal control over therapeutic activation remains a formidable challenge due to premature release, insufficient tumor specificity, and limited responsiveness to endogenous cues. Herein, we report a programmable nanocomposite featuring a three‐state transformation mechanism—resting, activated, and burst states—for controllable and efficient tumor treatment. The nanocomposite was constructed by coating the bacterial outer membrane vesicle (OMV) with a biocompatible dopamine–calcium carbonate (Da–Ca) shell, forming a stable structure under physiological conditions (resting state). Upon accumulation in the mildly acidic tumor microenvironment, the system transitions into an activated state, where internal destabilization occurs without disrupting the shell morphology. Subsequent near‐infrared (NIR) laser irradiation triggers a rapid transition to the burst state, resulting in complete shell disintegration and the synchronous release of OMVs and calcium ions. This cascade‐like activation enables synergistic photothermal therapy, calcium overload‐induced cytotoxicity, and immunotherapy via OMV‐mediated immune activation. The programmable nature of the system ensures precise tumor targeting, minimized systemic toxicity, and robust antitumor efficacy. This work provides a versatile platform for next‐generation nanotherapeutics with enhanced safety and multimodal therapeutic integration.