An Autophagy-Sensitive Nanoplatform via Chirality-Selective Modulation for Functional Peripheral Nerve Repair and Target Organ Homeostasis

Peripheral nerve injury (PNI) and diabetic peripheral neuropathy (DPN) are prevalent and destructive problems in clinical practice; however, there is currently no precise strategy for them despite a wide range of attempts due to their ambiguous neuromodulation effects. Accumulating evidence indicates the opposite functions of chiral enantiomers in various diseases, suggesting that chirality-selective modulation should be investigated. Herein, Fe₃O₄ nanoparticle enantiomers were synthesized to clarify the concept of chirality-selective neuromodulation, followed by mechanistic investigation. Nerve scaffolds loaded with different Fe₃O₄ enantiomers were implanted into rat models of PNI or DPN, followed by functional and morphological assessments. Transcriptomic and experimental analyses indicated that dextrorotatory Fe₃O₄ enantiomers (D-Fe₃O₄) were endocytosed by Schwann cells, promoting their proliferation, migration, and differentiation into the remyelinated phenotype through the autophagy-driven p-JNK/EPHA5 pathway. Furthermore, implants loaded with D-Fe₃O₄ exhibited more rapid structural reconstruction along with better sensory and locomotive restoration in the PNI and DPN models. The functional neural repair achieved through D-Fe₃O₄ led to maintenance of the morphology of target organs and limb health. Taken together, this study broadens our understanding of chirality-selective neuromodulation of chiral enantiomers and offers a promising approach with significant translational potential for functional nerve tissue repair and target organ homeostasis.