On-demand reprogramming of immunosuppressive microenvironment in tumor tissue via multi-regulation of carcinogenic microRNAs and RNAs dependent photothermal-immunotherapy using engineered gold nanoparticles for malignant tumor treatment

The frequent immune escape of tumor cells and fluctuating therapeutic efficiency vary with each individual are two critical issues for immunotherapy against malignant tumor. Herein, we fabricated an intelligent core-shell nanoparticle (SNAs@CCMR) to significantly inhibit the PD-1/PD-L1 mediated immune escape by on-demand regulation of various oncogenic microRNAs and perform RNAs dependent photothermal-immunotherapy to achieve precise and efficient treatment meeting the individual requirements of specific patients by in situ generation of customized tumor-associated antigens. The SNAs@CCMR consisted of antisense oligonucleotides grafted gold nanoparticles (SNAs) as core and TLR7 agonist imiquimod (R837) functionalized cancer cell membrane (CCM) as shell, in which the acid-labile Schiff base bond was used to connect the R837 and CCM. During therapy, the acid environment of tumor tissue cleaved the Schiff base to generate free R837 and SNAs@CCM. The SNAs@CCM further entered tumor cells via CCM mediated internalization, and then specifically hybridized with over-expressed miR-130a and miR-21, resulting in effective inhibition of the migration and PD-L1 expression of tumor cells to avoid their immune escape. Meanwhile, the RNAs capture also caused significant aggregation of SNAs, which immediately generated photothermal agents within tumor cells to perform highly selective photothermal therapy under NIR irradiation. These chain processes not only damaged the primary tumor, but also produced plenty of tumor-associated antigens, which matured the surrounding dendritic cells (DCs) and activated anti-tumor T cells along with the released R837, resulting in the enhanced immunotherapy with suppressive immune escape. Both in vivo and in vitro experiments demonstrated that our nano- particles were able to inhibit primary tumor and its metastasis via multi-regulation of carcinogenic microRNAs and RNAs dependent photothermal-immune activations, which provided a promising strategy to reprogram the immunosuppressive microenvironment in tumor tissue for better malignant tumor therapy.