Charge‐Guided Cartilage‐Penetrating Micro/Nanocarriers That Inhibit Piezo1 and Protect Cartilage to Alleviate Osteoarthritis

Abstract Osteoarthritis (OA), characterized by progressive cartilage degeneration and chronic joint pain, represents a major global health challenge. While intra‐articular drug delivery is a common therapeutic approach, its efficacy is limited by poor drug penetration through the dense cartilage matrix, particularly for hydrophobic compounds. Here, a novel charge‐guided micro/nanocarrier system designed to overcome these delivery challenges is presented. By modifying amylose with glycidyl trimethyl ammonium chloride (GTAC), it is developed positively charged carriers that demonstrate enhanced penetration into the negatively charged cartilage matrix. The hydrophobic Piezo1 inhibitor, Margaric acid (MA), is efficiently encapsulated within the helical cavity of modified amylose through DMSO‐ultrasound treatment, creating Cationic Amylose Micro/Nanocarriers@MA (CAMNC@MA). This system effectively delivers MA to chondrocytes, where Piezo1, a crucial mechanosensor implicated in OA development, can be precisely modulated. These results demonstrate that CAMNC@MA successfully inhibits abnormal mechanical force‐induced Piezo1 activation in chondrocytes, enhances cell survival, reduces matrix degradation, and effectively alleviates OA progression. This innovative drug delivery platform offers a promising strategy for clinical OA treatment by combining enhanced matrix penetration with efficient matrix penetration of hydrophobic therapeutic agents.