Dually tissue-anchoring platelets backpacking MDSC-derived extracellular vesicles to locally sustain immune reprogramming for inflammation resolution

Diverse immuno-inflammatory disorders are typically caused by dysregulated immunoactivation and the consequently chronic tissue inflammation. However, current therapeutics have exhibited mixed success due to either inherent inefficacy or limited localized tissue retention. Holistic approaches capable of integrating multipotent biotherapeutics with their optimized bioavailability in inflamed sites remain highly demanded for refractory inflammation management. Herein, dually matrix-binding platelet backpacking extracellular vesicles from myeloid-derived suppressor cells (A5/PLT-MDEV) is reported to mediate superior tissue residence of MDEVs to sustain localized immune reprogramming to durably alleviate inflammation. Scalability of the facile synthesis method, from using cell line-derived platelets to exploiting primary stem cell-derived platelets, has been demonstrated. Owing to integrin α5 overexpression and inherent characteristic, MDEV-decorated engineered platelets concurrently bind fibronectin and collagen in inflamed tissues, shelter MDEVs from macrophage uptake, and serve as micro-depots to confer on-demand release, collectively assisting backpacked MDEVs to reside locally for at least 10 days in mouse periodontitis and arthritis lesions. Such extended localized bioavailability of A5/PLT-MDEV enables a single dosage to allow MDEVs to lastingly reshape immune microenvironment in mouse periodontitis and arthritis, including upregulating Treg cells and suppressing pro-inflammatory T cells. Hence, A5/PLT-MDEV exhibits potent capacity in mitigating systemic and local inflammation. Compromised tissue homeostasis is consequently restored to rescue aggravation of these diseases. Dually tissue-anchoring platelet proposes a universal platform to develop spatiotemporally retaining therapeutics for safe and efficacious management of inflammation-accompanied conditions. • Dually-tissue anchoring platelets are engineered to be long-living platforms. • MDSC-derived extracellular vesicles mitigate inflammation via immunomodulation. • Platelets backpack MDEVs to sustain the local residence and therapeutic efficacy. • Platelet backpacking approach shows versatility and broad applicability potential.