A sonoelectric niche for noninvasive intervertebral disc regeneration via targeted cell cycle modulation.

Abstract

Cell cycle regulation is pivotal for tissue regeneration yet remains challenging in degenerative microenvironments. We engineered a sonosensitive conductive hydrogel incorporating polypyrrole-encapsulated porphyrin derivatives {[Tetrakis (4-carboxyphenyl) porphyrin (TCPP)]@PPy} to regulate cell cycle dynamics. Upon ultrasound irradiation, TCPP@PPy generates free electrons, establishing a controlled microcurrent within degenerative tissues. This sonoelectric niche induces nucleus pulposus cell (NPC) membrane depolarization, activating calcium voltage-gated channels (Ca_v) to drive Ca²⁺ influx. Subsequent calcium- and calmodulin-dependent protein kinase I activation up-regulates cyclin-dependent kinases CDK1/CDK2, forming a sonoelectricity-ion-kinase axis that stimulates NPC proliferation and anabolism. Concurrently, ultrasound-responsive borate ester bonds in the hydrogel amplify reactive oxygen species scavenging, counteracting oxidative stress-induced NPC ferroptosis. In a goat model of intervertebral disc degeneration, ultrasound-guided hydrogel implantation alleviated degenerative progression by synergistically reactivating cell cycle progression and suppressing oxidative damage. This strategy demonstrates a noninvasive, dual-targeted approach to regulate degenerative microenvironments through spatiotemporal control of sonoelectric and biochemical cues, offering a translatable strategy for tissue regeneration therapies.