Microfluidic Nanocomposite Lubricating Microgels Localized Deliver Celastrol for Remodeling the Immune...

In response to the disparity between the notable biological efficacy and systemic toxicity of celastrol (Cel), this study established a synergistic delivery system (Cel/Lipo+/BHMs) that integrates Bletilla striata polysaccharide (BSP) and hyaluronic acid biomimetic lubricating double-cross-linked microgels (BHMs) infused with Cel cationic liposomes (Cel/Lipo+). The objective is to collaboratively attain attenuation, sustained retention, and reconfiguration of the immunological milieu for the treatment of osteoarthritis. Cel/Lipo+ selectively targets chondrocytes via electrostatic interactions, hence improving Cel delivery and reducing off-target damage. Biolubrication by BHMs reduces friction and markedly extends the drug's retention duration within the joint cavity. In vitro studies have shown that Cel/Lipo+/BHMs possess excellent biocompatibility, enhance the proliferation and migration of chondrocytes, diminish oxidative stress, and work in conjunction with Cel/BSP to modulate macrophage reprogramming while suppressing the release of proinflammatory factors tumor necrosis factor-α and interleukin-1β. In a rat osteoarthritis model induced by monosodium iodoacetate, Cel/Lipo+/BHMs effectively mitigated cartilage degeneration by synergistically suppressing the inflammatory response, diminishing the expression of the cartilage degradation enzyme matrix metalloproteinase 13, enhancing the synthesis of type II collagen and aggrecan, and ameliorating subchondral bone microstructure. The therapeutic efficacy markedly exceeds that of either Cel/Lipo+ or BHMs individually, thereby emphasizing the primary benefits of the multitiered collaborative mechanism of the delivery system.