Photothermal modulation of the regenerative microenvironment for reversing optic nerve injury

Optic nerve injury (ONI) is a leading cause of irreversible vision loss worldwide, with no effective treatment strategies currently available in clinical practice. Efforts to promote visual protection and restoration have primarily focused on transforming the inhibitory extrinsic neural microenvironment into one that fosters neuro-regeneration. In this study, we pioneer a novel mild thermal stimulation therapy strategy based on polydopamine nanoparticles (PDA NPs) for ONI reversal. In vitro and in vivo studies demonstrated that PDA NP-mediated photothermal therapy effectively reduces excessive reactive oxygen species in retinal ganglion cells during acute injury phase, facilitates a shift in microglial phenotype from an injury-induced hyperactivated state to a repair-adaptive profile, thereby mitigating inflammatory responses. In the middle-to-late injury stages, near-infrared irradiation of PDA NPs induced localized warming in the eye, modulating astrocyte function, suppressing excessive or dysregulated deposition of extracellular matrix molecules under fibrotic conditions, and reducing neuroglial scar formation. These effects contribute to the establishment of a biofriendly extracellular matrix microenvironment. By restoring homeostasis in the optic nerve microenvironment in an optic nerve crush rat model, this approach enhances retinal ganglion cells survival, promotes axonal regeneration, and facilitates visual function recovery, ultimately achieving continuous neuroprotection throughout the injury process. Scheme. Schematic illustration of an ocular mild thermal stimulation therapy based on PDA NPs for reversing ONI. PDA NP-mediated PTT represents a promising neuroprotective strategy by addressing multiple pathological stages of ONI. During the acute phase, it efficiently scavenges excessive ROS in RGCs, facilitating the microglial transition from a hyperactivated, pro-inflammatory state to a reparative, adaptive phenotype, thereby attenuating the inflammatory storm. In the mid-to-late stages, NIR-triggered photothermal stimulation by PDA NPs induces localized heating in the eye, finely modulating astrocyte function and preventing the excessive or aberrant deposition of ECM components under fibrotic conditions. This process contributes to the establishment of a biofriendly ECM microenvironment, ultimately ensuring sustained neuroprotection throughout the entire course of ONI. • Engineered PDA NPs with NIR-I absorption and high photothermal conversion efficiency have been developed. • PDA NP-mediated PTT reconstructs regenerative microenvironment, enhancing RGC survival and axonal regeneration. • Dual-phase effects: acutely, PDA NPs modulate microglia to alleviate inflammatory storms; chronically, photothermal effects regulate astrocytes and remodel ECM to inhibit glial scar formation. • A spatiotemporally controlled PTT platform integrates material engineering to facilitate ONI repair and vision restoration.