Background/Objectives: Parkinson’s disease (PD) is a rapidly growing neurological disorder in the developed world, affecting millions over the age of 60. The decline in motor functions occurs due to a progressive loss of midbrain dopaminergic neurons, resulting in lowered dopamine levels and impaired muscle function. Studies show defective mitochondrial autophagy (or “mitophagy”) links to PD. Rho-associated coiled-coil containing protein kinases (ROCK) 1 and ROCK2 are serine/threonine kinases, and their inhibition can enhance neuroprotection in PD by promoting mitophagy. Methods: We examine the effects of ROCK inhibitor SR3677, delivered via macrophage-derived small extracellular vesicles (sEVs) to Parkin Q311X(A) PD mouse models. sEVs with SR3677, administered intranasally, increased mitophagy gene expression, reduced inflammatory factors, and elevated dopamine levels in brain tissues. Results: ROCK2 expression decreased, showing the drug’s inhibitory effect. sEV-SR3677 treatment was more effective than treatment with the drug alone, although sham EVs showed lower effects. This suggests that EV-SR3677 not only activates mitochondrial processes but also promotes the degradation of damaged mitochondria through autophagy. Mitochondrial functional assays and oxygen consumption in ex vivo glial cultures revealed that sEV-SR3677 significantly improved mitochondrial respiration compared to that in untreated or SR3677-only treated cells. Conclusion: We demonstrated the efficacy of ROCK2 inhibition on mitochondrial function via sEV-SR3677 in the PD mouse model, necessitating further studies to explore design challenges and mechanisms of sEV-SR3677 as mitochondria-targeted therapy for PD

Chimeric antigen receptor (CAR)-T cell therapy has demonstrated remarkable efficacy in hematologic malignancies; however, durable responses remain limited by tumor microenvironment (TME)-mediated immunosuppression. Galectin-3 (Gal-3), a β-galactoside-binding lectin enriched in the TME, contributes to CAR-T cell dysfunction by impairing cytotoxicity, promoting apoptosis, and altering cellular signaling. While we previously demonstrated that enforced expression of the α2,6 sialyltransferase ST6GAL1 reduces galectin binding and improves CAR-T cell function, the mechanistic basis underlying this protection remains unclear. Here, we report that Gal-3 induced a hypometabolic state in CAR-T cells characterized by reduced mitochondrial function, ATP production, and glucose utilization. In contrast, ST6GAL1-overexpressing CAR-T cells preserved metabolic fitness and functional resilience under Gal-3 stress. Additionally, Gal-3 rewired cytokine signaling by increasing IL-5 expression and dysregulating downstream pathways, whereas enforced ST6GAL1 expressing CAR-T cells exhibited increased SOCS1 and SOCS3 expression and attenuated STAT5 activation. Transcriptomic analysis of CAR-T cells from diffuse large B-cell lymphoma patients further revealed enrichment of STAT5-associated signaling and SOCS1 expression in complete responders compared to partial responders. Collectively, these findings identify glycoengineering as a promising strategy to enhance CAR-T cell persistence and function under Gal-3-mediated immunosuppressive stress.