PD-L1 antibody-modified plant-derived nanovesicles carrying a STING agonist for the combinational immunotherapy of melanoma

Combination therapies for melanoma face challenges due to asynchronous drug delivery and associated toxicity, underscoring the need for advanced delivery systems. While immune checkpoint inhibitors (ICIs) enhance T cell activity, optimal cytotoxic responses require efficient antigen presentation by mature dendritic cells (DCs), which are often functionally impaired in the tumor microenvironment. Thus, effective treatment requires coordinated T cell activation, DC-mediated priming, and direct tumor suppression. Herein, wild Glycyrrhiza uralensis Fisch roots-derived nanovesicles (GC NV) are demonstrated to be effective inhibitors of melanoma proliferation. The vesicles exert this activity through the intracellular delivery of encapsulated miRNA (miR2916) and bioactive molecules (isoliquiritigenin), with this capacity for intracellular delivery extending to the STING agonist DMXAA. We also demonstrate how chemical modification can be used to install PD-L1 antibodies on the membrane surface of these GC NV, imbuing these vesicles with selectivity for tumor cells. Combining DMXAA encapsulation with surface-displayed PD-L1 antibodies creates vesicles (GP@DMX NV) that both promote DCs maturation and elicit CD8 + T cell response. Our multifunctional GP@DMX NV reverse the immunosuppressive microenvironment of melanoma and significantly enhance the immunotherapeutic potential of immune checkpoints. This study developed an aPD-L1-armed GC NV-based immunotherapeutic platform for co-delivery of DMXAA, leading to reinvigorate immune states and sensitize tumors to immune checkpoint inhibitors. GC NV could inhibit melanoma proliferation and induce apoptosis by enriched miR2916 and isoliquiritigenin revealed by multi-omics sequencing. This plant-derived nanotherapeutic platform exhibited potent therapeutic efficacy against tumors, and is therefore a potential promising strategy for enhancing the clinical viability of immune checkpoint inhibitors. • GC NV are demonstrated to be effective inhibitors of melanoma proliferation. • PD-L1 antibody is firstly introduced into the surface of GC NV by DSPE-PEG linker,imbuing these vesicles with selectivity for tumor cells. • We develop aPD-L1-armed GC-NV-based immunotherapeutic platform collaborated with co-delivery of DMXAA (GP@DMX NV) for combinational immunotherapy of melanoma. • Mechanism of the antitumor effect of GP@DMX NV is uncovered by transferring the miRNA and bioactive ingredients.