Poly(N-isopropylacrylamide)-Grafted Hyaluronic Acid Semi-Gels for Localized Mitochondrial Transplantation in Spinal Cord Injuries

Mitochondrial transplantation (MT) represents a promising strategy for treating conditions associated with mitochondrial dysfunction, including neurodegenerative diseases, metabolic syndromes, and tissue regeneration scenarios such as spinal cord injury (SCI). Unlike conventional approaches that address symptoms, MT aims to restore cellular energy homeostasis by replacing impaired mitochondria with functional organelles. However, clinical translation has been limited by the short extracellular lifetime of isolated mitochondria and by their rapid dispersion from the injection site. To address these barriers, we developed a thermoresponsive carrier based on hyaluronic acid covalently grafted with poly(N-isopropylacrylamide) (HA-PNIPAAm), which combines the biocompatibility and bioactivity of HA with the temperature-induced chain collapse of PNIPAAm. The copolymers form injectable semi-gels that thicken above the transition temperature, resist dispersion under flow, and dissolve over hours to release their cargo. We characterized their composition, phase transition behavior, viscoelasticity, and mitochondrial release kinetics, and showed that encapsulation preserved mitochondrial respiratory function and membrane potential relative to free mitochondria over the time window relevant to delivery. In a rat contusion SCI model, subdural delivery of mitochondria in HA-PNIPAAm semi-gels restored spinal cord mitochondrial respiration to uninjured levels at 48 h post-injury. These findings establish HA-PNIPAAm semi-gels as a tunable, injectable platform for localized, cell-compatible mitochondrial delivery and support further evaluation of MT for SCI and other conditions characterized by mitochondrial dysfunction.