Lactate metabolism reprogramming through orthogonal tandem catalysis to reverse intervertebral disc degeneration.

Abstract

Lactate significantly accumulates in intervertebral disc degeneration (IVDD) to promote inflammation storm and nucleus pulposus cells (NPCs) senescence. However, eliminating the lactate efficiently and inhibiting the inflammation storm and NPCs senescence stimulated by lactate remains a challenge. Here, we show a lactate metabolism reprogramming reactor, which converts lactate to the inhibitor of NPCs senescence (alanine) through orthogonal tandem catalysis (OTC) reaction, thereby guiding the lactate metabolism reprogramming. Enzymes and substrates are encapsulated to prepare OTC nanoparticles, which are embedded in hydrogel microspheres to form the reactors. The lactate metabolism reprogramming efficiently performs in vitro and sustainably conducts in vivo to down-regulate lactate to reduce NLRP3 activity and up-regulate alanine to decrease oxidative stress, significantly inhibiting the inflammatory storm and NPCs senescence. The biomechanical function of neo-generated tissues reaches 94% of that of normal tissues, showing clinical potentials in reversing the IVDD.