Preferential Drug Loading into Platelet α Granules Boosts Inflammation‐Targeted Delivery in Rheumatoid Arthritis

ABSTRACT In rheumatoid arthritis (RA), circulating platelets (PLTs) migrate to the inflamed synovium and interact with inflammation‐resident cells, thereby amplifying inflammatory cascades. Moreover, these PLTs become overactivated and rapidly release α‐granule contents in response to an inflammatory stimulus. Thus, the preferential incorporation of therapeutics into α granules can facilitate inflammation‐homing trafficking and on‐demand drug release. Due to the close crosstalk between PLTs and multiple inflammation‐resident cells, precise modulation of PLTs dysfunction holds potential to inhibit the pathological cellular interaction and inflammatory cascades. Owing to the high P‐selectin expression on both PLT membranes and α granules, we synthesize a P‐selectin‐targeted and resveratrol (Res)‐loaded nanoparticle BFNPs@Res. After intravenous administration, BFNPs@Res selectively bind to circulating PLTs and accumulate in α granules. These BFNPs@Res‐incorporated PLTs subsequently migrate to the inflamed synovium and release therapeutic payloads stored in α granules responding to inflammatory stimulus. Meanwhile, after internalization by PLTs, BFNPs@Res effectively suppress pathological PLTs activation and disrupt their crosstalk with inflammatory cells. In arthritic rats, BFNPs@Res attenuate PLT‐mediated inflammatory cell recruitment and effectively alleviate RA symptoms. To our knowledge, this is the first report of exploiting the inflammatory homing and stimulus‐responsive α granule release of PLTs for inflammation‐targeted delivery, providing new insight for RA therapy.