Spatial control of gene expression is critical to modulate cellular functions and deconstruct the function of individual genes in biological processes. Light-responsive gene-editing formulations have been recently developed; however, they have shown limited applicability in vivo due to poor tissue penetration, limited cellular transfection and the difficulty in evaluating the activity of the edited cells. Here, we report a formulation composed of upconversion nanoparticles conjugated with Cre recombinase enzyme through a photocleavable linker, and a lysosomotropic agent that facilitates endolysosomal escape. This formulation allows in vitro spatial control in gene editing after activation with near-infrared light. We further demonstrate the potential of this formulation in vivo through three different paradigms: (i) gene editing in neurogenic niches, (ii) gene editing in the ventral tegmental area to facilitate monitoring of edited cells by precise optogenetic control of reward and reinforcement, and (iii) gene editing in a localized brain region via a noninvasive administration route (i.e., intranasal).

Stroke is a leading cause of death worldwide and poses significant societal and healthcare challenges due to functional impairment of the brain. In order to fully restore brain function, innovative approaches have aimed to regenerate the injured tissue and to restore neuronal circuitry. In the last 5 years, stem cells have been consistently explored in clinical trials for tissue regeneration. Recent technological progress regarding the use of stem cell-derived extracellular vesicles has also shown promise toward the administration of cell-based therapies exploiting paracrine signaling. In addition, neuromodulation using different stimulation modalities has become increasingly investigated in the clinic as a non-invasive strategy to promote functional recovery. This approach contrasts with invasive strategies using devices capable of delivering electrical pulses in deep regions of the brain, which nonetheless are well-established in the clinic for the treatment of other neurological disorders. This chapter reviews the latest approaches covering brain tissue regeneration and neuromodulation, and discusses their limitations for clinical translation. Preclinical investigations on the use of light for neuromodulation in optogenetics have sparked the development of biocompatible interfaces capable of coupling optical stimulation with electrical recording. These biointerfaces require novel materials whose physicochemical properties are discussed herein.

Neurological disorders are one of the world’s leading medical and societal challenges due to the lack of efficacy of the first line of treatments. Although pharmacological and non-pharmacological interventions have...

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