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

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.