Nanoparticle-based optical interfaces for retinal neuromodulation: a review

Abstract

Degeneration of photoreceptors in the retina is a leading cause of blindness, but commonly leaves the retinal ganglion cells (RGCs) and/or bipolar cells extant. Consequently, these cells are an attractive target for the invasive electrical implants colloquially known as "bionic eyes." However, after more than two decades of concerted effort, interfaces based on conventional electrical stimulation approaches have delivered limited efficacy, primarily due to the current spread in retinal tissue, which precludes high-acuity vision. The ideal prosthetic solution would be less invasive, provide single-cell resolution and an ability to differentiate between different cell types. Nanoparticle-mediated approaches can address some of these requirements, with particular attention being directed at light-sensitive nanoparticles that can be accessed via the intrinsic optics of the eye. Here we survey the available known nanoparticle-based optical transduction mechanisms that can be exploited for neuromodulation. We review the rapid progress in the field, together with outstanding challenges that must be addressed to translate these techniques to clinical practice. In particular, successful translation will likely require efficient delivery of nanoparticles to stable and precisely defined locations in the retinal tissues. Therefore, we also emphasize the current literature relating to the pharmacokinetics of nanoparticles in the eye. While considerable challenges remain to be overcome, progress to date shows great potential for nanoparticle-based interfaces to revolutionize the field of visual prostheses.

Keywords: nanoparticle transducers; neuromodulation; optical nanosensors; retinal degeneration; retinal pharmacokinetics; retinal prosthesis.

Figure 1

The structure of the eye and retina. Adapted from Kandel (2014), created in BioRender.com (2023).

Figure 2

Retinal circuitry: ON and OFF pathways in the retina. RBC, rod bipolar cell; CNC, cone bipolar cell; HC, horizontal cell; AII, AII amacrine cells; GC, ganglion cell; IPL, inner plexiform layer; GCL, ganglion-cell layer; INL, inner nuclear layer; ONL, outer nuclear layer; OPL, outer plexiform layer; OS, outer segments of photoreceptor. Reproduced under the terms of the Creative Commons Attribution License, from Fain and Sampath (2018).

Figure 3

Schematics of biophysical mechanisms for optical and ultrasonic modulation. (A) Activation of genetically-modified channels. Left, middle: activation of light-sensitive channels channelrhodopsin-2 (ChR2) and halorhodopsin (HALO); right: activation of ultrasound sensitive proteins (SON, includes TRPV1 ion channels, mechanosensitive ion channel of large conductance – MscL, or auditory-sensing protein prestin). (B) Infrared neural modulation. Left: localized heating; middle: closed thermally-mediated TRPV channel; right: activation of thermally-mediated TRPV channel. (C) Ultrasonic stimulation. Left: Change in the membrane conformational state causes activation of voltage-gated channel; middle: thermodynamic waves; right: activation of mechanosensitive channel. (D) Ultrasonic stimulation causing cavitation effects. (E). Nanoparticle-mediated stimulation. Left: localized heating; middle: activation of TRPV channels; right: nanoparticles generating a dipole moment. (F) Photochemical tools. Left: photocaged neurotransmitters; right: photoswitches responding to a particular wavelength of light. Created in BioRender.com (2023).

Figure 4

(A) Routes of administration for retinal drug delivery. (B) Blood-ocular barriers. Created in Biorender.com (2023).