Cancer Cell Membrane‐Coated Nanoparticles for Homotypic Targeting and Photothermal Chemo‐Immunomodulatory Therapy of Oral Cancer

The integration of chemotherapeutics with photothermal immunomodulatory strategies, leveraging a nanotechnology platform, has transformative potential for cancer therapy. In this context, we have designed a novel biomimetic platform by cloaking Palbociclib-loaded mesoporous silica-polypyrrole nanoparticles with homologous cancer cell membranes (CM@SP-PLB NPs). These biomimetic NPs exhibit optimal physicochemical characteristics, including uniform morphology, laser-responsive drug release, and a photothermal efficiency of 57.6%. In vitro assays demonstrate enhanced homotypic cellular uptake, reactive oxygen species (ROsS) generation, mitochondrial dysfunction, and potent cytotoxicity in human and murine oral cancer cells. Additionally, they induce the release of immunogenic cell death (ICD) markers via exposure of the surface marker calreticulin (CALR) and extracellular ATP release. CM@SP-PLB NPs (+L) exhibited superior tumor accumulation, photothermal effects, and increased temperature up to 55°C, resulting in effective tumor volume regression. In vivo immunomodulation studies showed tumor-associated macrophage repolarization and significant immunomodulatory reprogramming by downregulating immunosuppressive markers while markedly upregulating key pro-inflammatory and antitumor immune genes, thereby enhancing the antitumor immune response. Furthermore, systemic biocompatibility and reduced metastasis further substantiate the nanoplatform's therapeutic potential. Overall, the developed bioinspired nanoplatform offers a chemo-immunomodulatory photothermal strategy for synergistic eradication of tumors in oral cancer.