Phosphatidylserine decorated inhalable immunostimulants to eradicate pulmonary metastasis through alveolar macrophage polarization and phagocytosis restoration in situ

Abstract

Pulmonary metastasis is frequently observed across various malignant tumors, contributing to a considerable mortality and featuring with a low immune response rate. In this work, a pathological analysis of the pulmonary metastasis indicates that alveolar macrophages (AMs) are prone to be polarized into immunosuppressive M2 phenotype, and the drug screening confirms that TLR7/8 agonists (R848) and SHP2 inhibitor (SHP099) would polarize AMs into immune-promoting M1 phenotype and restore their phagocytic elimination behavior. Based on these discovery, Inhalable and Alveolar Macrophage targeted IMmunostimulants (designated as I-AM-IMs) are fabricated by using phosphatidylserine decorated liposomes to co-deliver R848 and SHP099. Nebulization inhalation of I-AM-IMs enables the passive and active targeted drug delivery for AMs resided in lower respiratory tract, promoting AMs polarization and phagocytosis restoration in situ. Meanwhile, phenotype reprogramming of AMs could direct the phagocytic elimination of pulmonary metastatic tumor cells, trigger the release of cytotoxic cytokines and activate CD8 T cell specific anti-tumor immunity. In vitro and in vivo studies demonstrate the superior immunotherapeutic effects of I-AM-IMs to eradicate pulmonary metastasis, which might provide a versatile and effective strategy for localized pulmonary metastasis immunotherapy.