Tumor‐Specific Photothermal‐Therapy‐Assisted Immunomodulation via Multiresponsive Adjuvant Nanoparticles

Multiresponsive adjuvant nanoparticles (RMmAGL) are fabricated to perform tumor-specific photothermal therapy while regulating the behavior of tumor-associated immune cells for primary tumor eradication and metastasis inhibition. Core-satellite-like RMmAGL have a core of mannose-functionalized mesoporous silica nanoparticles loaded with the TLR7 agonist imiquimod (R837@MSN-mannose) connected via hydrazone bonds to satellites of glutamine (Glu)- and lysine (Lys)-comodified gold nanoparticles (AuNPs-Glu/Lys). During therapy, the acidic environment in tumor tissue cleaves the hydrazone bonds to release AuNPs-Glu/Lys, which further accumulate in tumor cells. After internalization, photothermal agents (aggregated AuNPs-Glu/Lys) are generated in situ through the intratumoral enzyme-catalyzed reaction between Glu and Lys, resulting in tumor-specific photothermal therapy. The detachment of AuNPs-Glu/Lys also triggers the release of R837, which matured dendritic cells (DCs) via a vaccine-like mechanism along with the tumor-associated antigens generated by photothermal therapy. These matured DCs further activates surrounding T cells for immunotherapy. Moreover, the resulting free MSN-mannose serves as an artificial glycocalyx to continuously induce the polarization of tumor-associated macrophages from an immunosuppressive phenotype to an inflammatory phenotype, thus further enhancing immunotherapy. Both in vivo and in vitro experiments demonstrate significant inhibition of malignant tumors after therapy.