Microalgae-Derived Extracellular Vesicles Synergize with Herbal Hydrogel for Energy Homeostasis in Osteoarthritis Treatment

Treatment of osteoarthritis (OA) remains challenging owing to its complex pathological microenvironment, which involves reactive oxygen species, chronic inflammation, mitochondrial dysfunction, energy deficiency, and cartilage degeneration. Herein, we report for extracellular vesicles (SP-EVs) derived from the photosynthetic microorganism <i>Spirulina platensis</i> contain antioxidative and ATP-dependent active and metabolic-related compounds for OA treatment. SP-EVs were effectively delivered to chondrocytes, demonstrating the potential for modulating cellular communication and energy homeostasis. To facilitate sustained delivery of SP-EVs, the rhein hydrogel system was used for intra-articular injection (Rh Gel@SP-EVs), which demonstrated pH responsiveness under mildly acidic conditions and synergistic anti-inflammatory effects. Rh Gel@SP-EVs significantly rescued mitochondrial dysfunction by ameliorating inflammation-mediated oxidative stress and restoring the mitochondrial membrane potential in chondrocytes. Improved mitochondrial function facilitates the replenishment of ATP levels, further contributing to the balance of anabolic and catabolic processes within the cartilage matrix, eventually decelerating OA progression. Rh Gel@SP-EVs also modulated the Janus kinase-signal transducer and activator of transcription 3 signaling pathway, implicated in suppressing inflammatory responses. This therapeutic strategy utilized a microalgae-based herbal hydrogel system to modulate the sustained release of SP-EVs, offering an effective approach for treating OA by regulating energy metabolism and anti-inflammatory mechanisms.