LIGHT-DRIVEN CORTICAL STIMULATION BY P3HT NANOPARTICLES RESTORES VISUAL RESPONSES IN THE RD10 MOUSE MODEL OF BLINDNESS

Blindness remains a major unmet medical need, particularly when vision loss arises from damage in the visual pathways downstream of photoreceptors. Retinal ganglion cell loss and optic nerve degeneration underlie irreversible visual deficits under conditions such as glaucoma, ischemic optic neuropathy, and diabetic neuropathy, where conventional retinal prostheses are ineffective because the visual pathway is compromised [Zhang Z et al. 2026]. Conjugated polymer nanoparticles composed of poly(3-hexylthiophene) (P3HT NPs) confer light sensitivity to degenerated retinas and restore subcortical, cortical, and behavioral visual responses following subretinal injection in rodent models of retinal dystrophy [Francia S et al. 2022, Mantero G et al. 2026 in press]. Here, we investigated whether light-driven P3HT NPs can photosensitize cortical neurons in vivo and support visual recovery in the rd10 mouse model of blindness when delivered to the primary visual cortex (V1). In healthy wild-type mice injected with P3HT NPs in V1, trans-cortical laser illumination elicited phosphene-like perceptual responses in a custom conditioning paradigm, similar to those elicited by ambient light stimuli. Two-photon calcium imaging in vivo revealed robust light-evoked calcium responses in cortical neurons in contact with P3HT NPs, indicating effective photostimulation. Moreover, in rd10 mice with advanced photoreceptor degeneration, stimulation of cortically injected P3HT NP in V1 partially rescued visual responses compared to controls. These findings demonstrate that P3HT NPs can be exploited to enable light-dependent modulation of visual cortical activity, offering a promising strategy for vision restoration when cortical stimulation represents the only viable therapeutic option.