Nano-in-Micro GelMA depots assist electro-thermal-immuno orchestral treatment for solid triple negative breast tumor.

Triple-negative breast cancer (TNBC) exhibits high local-recurrence risk despite modern systemic therapy assisted with surgery or irradiation therapy. Here, we report an injectable nano-in-micro microsphere depot (cPAG) that integrates conductivity enhancement, photothermal conversion, O2 and reactive oxygen species (ROS) generation, and innate immune agonist co-delivery to support staged, local multimodal therapy. Monodispersed Au@GelMA microspheres prepared via microfluidics and photocrosslinking reduced high electrostatic resistance of GelMA hydrogels and provided stable 808 nm laser-responsive heating. The porous surface possessed abundant electrostatic adsorption sites for loading MnOx nanoflowers and anionic stimulator of interferon genes (STING) agonist. MnOx nanoflowers catalyzed H2O2 to generate O2, produced free radical signals and increased pro-inflammatory cytokines secretion in vitro. Co-delivery of agonist and MnOx nanoparticles further increased interferon-β secretion, consistent with induction of type I interferon response. In a 4T1 residual-tumor model established by partial tumor resection, a staged regimen consisting of cPAG-assisted irreversible electroporation followed by cPAG-mediated photothermal therapy showed the strongest suppression of local tumor regrowth among tested groups, with maintained body weight during the study window. Overall, cPAG provides a modular nano-in-micro depot strategy to integrate multiple local treatments for postoperative control of TNBC tumor.