Engineered Platelets Backpacking Immunotherapeutic Exosomes To Locally Sustain Inflammation Resolution

Dually tissue-anchoring platelet backpacking exosomes from myeloid-derived suppressor cells is developed to mediate the superior tissue residence of exosomes for sustained immunomodulatory effects to rescue the aggravation of various inflammatory diseases. Exosomes from MDSCs are decorated onto integrin α5 overexpressed platelets through matrix metalloproteinase-cleavable peptide linkers (A5/PLT-MDEV). The anti-uptake activities of raw 264.7 macrophages are studied by flow cytometry and confocal imaging. Tissue-retaining performances are studied in vitro models of inflamed gingival cryo-sections and mouse models of periodontitis and arthritis that are subjected to singly dosed fluorescent formulations and further detection via IVIS. Immunomodulatory effects and anti-inflammation efficacy of singly dosed A5/PLT-MDEV in these models are evaluated via flow cytometry, micro-CT and histological analysis. Owing to genetic manipulation and inherent characteristic, exosome-backpacked engineered platelets concurrently bind fibronectin and collagen in inflamed tissues, shelter MDEVs from macrophage uptake and confer on-demand release, collectively assisting MDEVs to reside locally for at least 10 days in mouse periodontitis and arthritis lesions. Therefore, A5/PLT-MDEV enables a single dosage to versatilely and potently reprogram immune microenvironment in mouse periodontitis and arthritis. Hence, A5/PLT-MDEV exhibits robust capacity in mitigating systemic and local inflammation to rescue compromised tissue homeostasis in these diseases. Engineered platelets serve as a universal platform to assist immunotherapeutic exosomes to spatiotemporally reside in inflamed tissues, disclosing translational potential for wide-ranging inflammation-accompanied conditions.