A composite peptide-supramolecular microneedle system for melanoma immunotherapy

Despite recent advances in melanoma treatment through the use of antibody immunotherapy, the clinical benefit remains restricted by its inefficient infiltration and immunosuppression within the tumor microenvironment (TME). In addition, immune-related adverse events (irAEs) have often occurred due to the off-target binding of therapeutic drugs to normal tissues after systematic administration. Herein, we constructed an integrated and cascaded drug delivery system for the treatment of melanoma. In addition to blocking the programmed cell death protein 1 or its ligand (PD-1/PD-L1) axis, the PD-L1 targeting peptide (FE) with spherical micelle self-assembly characteristics could also effectively encapsulate the immune adjuvant resiquimod (R848), and form a complete nano drug. FE^R was further integrated into tumor-responsive microneedles (MNs) to establish FE^R@MN and could reach the cascaded functions. FE^R could be sustainedly released from the MN system and disassemble into monomers, achieving PD-1/PD-L1 axis blockade whilst reprogramming the immunosuppressive TME. Notably, FE^R@MN permits the controllable release and retention enhancement of the targeting peptide in the TME, thus causing prolonged PD-L1 blockade effect. It is demonstrated that this synergistic treatment could efficiently inhibit melanoma growth, providing a new strategy for the combination treatment of melanoma. [Figure not available: see fulltext.].