Cationized gelatin nanosphere-mediated release-controlled RNA interference targeting mTORC1 protects against intervertebral disc degeneration.

Intervertebral disc degeneration is a major cause of chronic low back pain, but effective disease-modifying therapies remain unavailable. Sustained and localized RNA interference (RNAi) offers a promising therapeutic approach; however, its application to the disc is limited by poor local retention and delivery-related toxicity. Here, we developed a release-controlled RNAi platform using biodegradable cationized gelatin nanospheres (cGNS) to deliver small interfering RNA (siRNA) targeting Rptor, which encodes RPTOR, a key component of the mechanistic target of rapamycin complex 1 (mTORC1). cGNS enabled longer-term intracellular siRNA retention with lower toxicity than conventional lipofection, leading to a prolonged decrease in RPTOR expression, autophagy activation, and suppressed apoptosis, senescence, and matrix breakdown. Intradiscal delivery of Rptor siRNA with cGNS preserved radiographic tissue morphology, maintained histological matrix integrity, and reduced cellular degeneration markers. Benefits were observed in both preventive and post-traumatic settings. cGNS-mediated controlled release of RNAi against Rptor is a durable therapeutic strategy for degenerative disc disease through mTORC1 inhibition.