Delivery of Peptide-LYTAC via Polyporus Polysaccharide Microneedles for Targeted CD47 Degradation and Enhanced Tumor Immunotherapy.

Targeting immune checkpoints, such as CD47, holds promise for overcoming immune evasion in cancer, but current therapies face challenges related to toxicity and limited efficacy. Here, we develop a novel dissolvable microneedle (MN) platform that integrates a CD47-targeting peptide-based LYTAC (RS17-M6P₃) and polyporus polysaccharide (PPS) to simultaneously induce immune checkpoint degradation and reprogram the immunosuppressive tumor-associated macrophage microenvironment. The RS17-M6P₃ peptide is designed for efficient CD47 degradation in vitro and in vivo via the lysosomal pathway without significant toxic effects on red blood cells. PPS, a natural immunomodulator, enhances macrophage polarization from an M2 (immunosuppressive) to an M1 (pro-inflammatory) phenotype, further boosting macrophage-mediated phagocytosis of tumor cells. When incorporated into a dissolvable MN platform, RS17-M6P₃ and PPS work synergistically to augment antitumor immunity. In both melanoma and breast cancer mouse models, PPS/RS17-M6P₃-loaded microneedles effectively suppressed tumor growth, accompanied by enhanced immune activation and improved antitumor efficacy. This innovative MN-based delivery system provides a safer and noninvasive strategy for cancer immunotherapy by combining immune checkpoint degradation with immune modulation, laying the groundwork for the development of peptide-based LYTACs and natural polysaccharides as potent cancer therapies.