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

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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.