Liberación sostenida de PDGF-BB en microesferas controlada por luz NIR a largo plazo para aliviar la osteoartritis...

Intra-articular injection (IA) is a key method for drug administration in the treatment of osteoarthritis (OA). However, drugs given through this route are rapidly cleared by the synovium, reducing drug bioavailability and necessitating frequent injections. Additionally, the degree of articular cartilage damage varies among OA patients, highlighting the urgent need for a smart, controlled drug delivery system that responds to OA progression. Platelet-derived growth factor-BB (PDGF-BB) promotes chondrogenesis and has therapeutic potential for OA treatment, but its short half-life within the articular cavity limits its effectiveness.

PDGF-BB was bound to two-dimensional black phosphorus nanosheets (2D BPNSs) via electrostatic interactions. The morphology of BPNSs and PB@BPNSs was characterized using the transmission electron microscope. Zeta dynamic light scattering was used to assess their polydispersity index and zeta potential. Energy-dispersive X-ray spectroscopy elemental mapping and ELISA assays were performed to verify the binding efficacy. PB@BPNSs@CS was fabricated using an oil-in-water-oil double-emulsion method. ELISA assays were conducted to assess the capacity for sustained and controllable release. Cell Counting Kit-8 assay was used to evaluate the biocompatibility of PB@BPNSs@CS with ATDC5 cells. A mouse OA model was constructed through destabilization of the medial meniscus surgery. Safranin O-fast green staining, immunochemistry, and alcian blue staining assays were used to assess the therapeutic efficacy of PB@BPNSs@CS on OA. Additionally, human cartilage samples were analyzed to further confirm these findings and to assess the therapeutic potential of the identified signaling pathways. Western blot and immunofluorescence assays were conducted to explore the underlying molecular mechanism.

PB@BPNSs@CS enables a long-term sustained release of PDGF-BB for over five months and achieves NIR-light-controlled release. Importantly, a single administration of PB/BPNSs/CS alleviates OA symptoms in mice. Mechanistically, PDGF-BB promotes chondrogenesis by activating the PI3K/AKT signaling pathway, which subsequently inhibits GSK-3β and ultimately reduces SOX9 degradation in cultured chondrogenic cells and mouse OA. Furthermore, in human OA cartilage tissues, the levels of phosphorylated AKT, phosphorylated GSK-3β, and SOX9 are reduced.

The PI3K/AKT/GSK-3β/SOX9 axis plays an important role in OA. PB@BPNSs@CS sustains the release of PDGF-BB, enhances its bioavailability, and promotes its therapeutic efficacy in OA through a single dosage by inhibiting SOX9 degradation via the PI3K/AKT/GSK-3β axis. Notably, the therapeutic efficacy of PB@BPNSs@CS can be controlled with a near-infrared laser.