Biomimetic Tryptophan-derived Carbon Dots as Nano-inhibitors to Reprogram Tryptophan-IDO1 Metabolic Axis for Peripheral Nerve Regeneration

Abstract

Peripheral nerve injury (PNI) remains a challenge in clinic with limited therapeutic options, where pathological disturbance of glial cells severely impedes axonal regeneration and functional recovery. Herein, the tryptophan (TRP)/indoleamine 2,3-dioxygenase 1 (IDO1)/kynurenine (KYN) metabolic axis was clarified to trigger Schwann cells (SCs) dysfunction by depletion of neuroprotective 5-hydroxytryptamine and accumulation of neurotoxic quinolinic acid. To rectify this abnormal metabolism, for the first time, we proposed a TRP-heritable mimicry (THM) strategy, and a series of biomimetic tryptophan-derived carbon dots (TNDs) were synthesized through mild non-enzymatic catalytic oxidation and Schiff-base reaction, which retained the enzyme recognition groups of TRP but not involved in TRP metabolism. Specifically, an estimated 2.83-fold higher binding affinity for IDO1 than free TRP was achieved by Li + -doped TNDs (TLNDs), which could effectively redirect TRP metabolic flux, activate NRF2-HO1 antioxidant axis in SCs with an IDO1-dependent manner, indicating that TLNDs could serve as a competitive IDO1 nano-inhibitor. Moreover, the TLNDs preferentially accumulated in lysosomes upon lipid raft-mediated endocytosis, where acid-responsive released Li + stimulated SCs autophagy and enhanced TFEB-mediated lysosomal biogenesis to accelerate lipophagy and cholesterol transport. In a rat sciatic nerve crush model, subepineurial TLNDs injection significantly suppressed neuroinflammation, promoted myelination, and ultimately led to favorable motor function recovery. This study identified IDO1-mediated TRP metabolic reprogramming as a critical PNI therapeutic target and provided a novel carrier-free specific IDO1-inhibition strategy for synergistic metabolic regulation and SCs functional activation to boost nerve regeneration, which also presented broad prospects in the field of central nervous system disease.

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