Neutrophil membrane biomimetic nanoparticles encapsulating kartogenin promote articular cartilage regeneration

Articular cartilage defect (ACD) is a refractory disease in sports medicine with poor self-healing ability, mainly due to inflammatory infiltration and insufficient chondrogenic differentiation of mesenchymal stem cells (MSCs). Conventional drug delivery systems suffer from poor absorption, rapid immune clearance and low targeting efficiency. Neutrophil membrane biomimetic nanoparticles hold great potential for targeted anti-inflammation and sustained drug delivery, while kartogenin (KGN) is a potent chondrogenic inducer. This study aimed to develop a neutrophil membrane-camouflaged KGN-loaded PLGA nanoparticle (KGN-NNPs) for ACD repair.

KGN-NNPs were fabricated by wrapping neutrophil membranes onto KGN-loaded PLGA nanoparticles. Physicochemical properties were characterized by TEM, DLS, zeta potential, WB and drug release assays. In vitro biocompatibility was evaluated by Live/Dead staining, CCK-8 and cytoskeleton staining. Anti-inflammatory effects were assessed using ELISA, immunofluorescence and qRT-PCR in LPS-induced inflammatory MSCs. Chondrogenic capacity was determined by qRT-PCR, WB and histological staining. A rat ACD model was established to verify in vivo cartilage regeneration via macroscopic observation, micro-CT, histological scoring and immunohistochemistry.

KGN-NNPs exhibited uniform spherical morphology with typical core-shell structure, stable size and zeta potential, and retained neutrophil membrane markers (TNF-α R, CD11b). Sustained KGN release over 30 days and pH-responsive release behavior were observed. KGN-NNPs showed excellent biocompatibility without cytotoxicity to MSCs. In vitro, KGN-NNPs significantly reduced TNF-α, IL-1β and IL-6 expression and effectively promoted MSCs chondrogenic differentiation by upregulating COL-2, SOX-9 and Aggrecan. In vivo, KGN-NNPs remarkably enhanced cartilage and subchondral bone regeneration, with higher ICRS scores, lower Wakitani scores, and increased type II collagen and proteoglycan deposition compared with other groups.

Neutrophil membrane-camouflaged KGN-NNPs possess good biocompatibility, targeted anti-inflammatory activity and strong chondrogenic induction ability. This biomimetic nanodrug delivery system significantly promotes articular cartilage regeneration in rat ACD model, providing a novel and promising strategy for the treatment of ACD.