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

Abstract 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.