A Mitochondria‐Specific Nanomedicine for Synergistic Chemo‐Photothermal Therapy and Immunogenic Activation Against Breast Cancer

The presence of "cold" tumors in the tumor site is characterized with poor immune cell infiltration and resistance to conventional cancer therapies. To address these challenges, we developed an amphiphilic peptide dendrimer-based multifunctional drug delivery system for integrating photothermal therapy (PTT), chemotherapy, and immunogenic cell death (ICD) to overcome the limitations of single-modality treatments. Efficient drug delivery via the nanoplatform is realized through improving circulation stability, facilitating accumulation and penetration in tumor tissues, promoting cellular uptake, and accelerating tumor microenvironment-responsive drug release. The mitochondria-targeting property is derived from a mitochondria-specific photothermal agent and a lipophilic cationic structure in the amphiphilic dendrimer, and it allows selective mitochondrial accumulation and disruption of the mitochondrial function. In vivo and in vitro studies confirm that PTT synergizes with chemotherapy to significantly enhance therapeutic efficacy, effectively induce ICD to modulate the tumor microenvironment, and strengthen antitumor responses. This nanoplatform enhances drug delivery, induces mitochondrial dysfunction, and achieves potent therapeutic effects, therefore, it could be fine-tuned to become versatile for combination cancer therapies.