Biomineralized Shewanella Exploits Tumor Lactate Metabolism via Biological Nanowires for Radiotherapy-Synergized...

Bioelectronic therapy is an emerging strategy that ablates tumor cells via electrical signals. However, achieving precisely controllable bioelectronic ablation remains challenging. Here, we report a living bioelectronic platform, termed PSDT, for radiotherapy (RT)-activated tumor intervention and immune activation. PSDT consists of a Pd/Pt-modified Shewanella core (SDT) encapsulated within a ROS-responsive polymeric shell (PEI-Se-Se-PEG). The ROS-responsive shell keeps the platform inert systemically and confines its activity to irradiated tumors, achieving spatiotemporal control. Upon RT activation, the released SDT core utilizes the anaerobic characteristics of the tumor microenvironment to specifically construct nanowire connections with tumor cells, thereby establishing the electronic synapse for current delivery. Simultaneously, the Pd/Pt bio-alloy enhances Shewanella's lactate metabolism and electron transfer. This enhancement enables the platform to generate a continuous bioelectric current fueled by tumor lactate. RT also induces the Pd/Pt bio-alloy to release high-energy electrons, which are then delivered to the tumor cells alongside the amplified bioelectric current through the nanowire. This dual-pathway electron delivery enhances tumor cell ablation and yields prominent inhibition of primary tumor growth. The treatment also induces systemic antitumor effects, as the release of tumor antigens from electro-ablation and bacterial antigens from RT-mediated bacterial disruption triggeres local immune activation and an abscopal effect. Moreover, the combination with anti-PD-1 treatment further enhances these effects, resulting in nearly complete tumor eradication and durable tumor control. This work demonstrates a bioelectronic therapy that integrates tumor metabolic intervention with systemic immune activation for the treatment of immunologically cold solid tumors.