Optogenetics, an interdisciplinary field combining optical engineering and genetic principles, is a cutting-edge biotechnology that enables precise spatiotemporal manipulation of cellular activity through light-gated modalities. The core of this technology is the genetic integration of photoreceptor proteins (e.g., microbial opsins, phytochromes) into target cells, allowing rapid and cell-type-specific functional modulation upon illumination with defined wavelengths [1], [2]. Since its inception, optogenetics has revolutionized various fields, including neural circuit dissection, pathophysiology modeling as well as the development of novel therapeutic paradigms, while consistently demonstrating expansive translational potential.

Technological advancements in optogenetic actuators and wavelength-selective delivery systems have driven their applications across neuroscience, cell biology and synthetic biology. In addition to providing transformative tools for fundamental biological exploration, optogenetics has accelerated clinical innovation, particularly in neurotherapeutics and precision cell-based interventions [3], [4], [5]. The safety and efficacy of optogenetic protocols have been rigorously validated in non-human primate models (e.g., macaque cortical-basal ganglia networks), establishing a critical translational bridge for elucidating the fundamental mechanisms of human brain function and neuropsychiatric disorders. Advancements in closed-loop optogenetic systems and minimally invasive interfaces are poised to further expand their interdisciplinary impact, offering unprecedented precision in decoding biological complexity and engineering novel therapeutic methods.

The core of the operational framework of optogenetics is photoreceptor proteins [[6], [7]], which act as molecular transducers, converting photonic stimuli into reversible biochemical cascades. Upon wavelength-specific illumination, these genetically encoded actuators orchestrate spatiotemporally precise modulation of cellular activity via conformational switching mechanisms. The channelrhodopsin variant, Chrimson, exhibiting peak activation under red-shifted illumination (590-630 nm), induces rapid neuronal depolarization via cation influx, with instantaneous recovery of excitability upon light cessation [[8], [9]]. In parallel, the optogenetically controlled receptor tyrosine kinase (opto-RTK) system achieves light-dependent receptor dimerization to activate mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK) signaling cascades, thereby modulating cellular proliferation or differentiation trajectories, while inactivating the signaling pathways under dark conditions through light-dependent receptor dissociation [10]. Compared with the conventional chemical induction methods, optogenetic technology stands out for its high biocompatibility (low or negligible toxicity), reversibility, temporal precision and sustainable operational stability, thereby cementing its dominance in animal cell experimentation [[11], [12]]. Although optogenetic tools by using blue or ultraviolet light have achieved broad applications, their clinical translation remains constrained by inherent limitations, including phototoxicity and restricted tissue penetrability [13]. In contrast, red light-responsive optogenetic systems exhibit superior biocompatibility (negligible toxicity), high induction fold-changes, deep tissue penetration, non-invasiveness and spatiotemporally precise control of gene expression. These advantages attribute to the establishment of red light as a transformative induction modality, offering novel strategies for the optical regulation of gene expression and expanding the research field of gene regulation. Red light optogenetics has demonstrated transformative applications across various domains, including oncotherapy and plant biotechnology. Notably, light-controlled modulation of phytochrome-mediated gene expression has emerged as a powerful approach for investigating dynamics of development, metabolic pathway regulation and environmental stress adaptation of plants [7]. Moreover, engineered light-gated channel proteins enable neuronal excitation or silencing via optical control of ion channel functions, thereby establishing a versatile platform for precise control of neuronal activity and developing neuromodulation-based therapeutics.

This review systematically describes the techniques enabling red/far-red light optogenetic interventions, focusing on their biomedical translational potential in regulation of gene expression, gene editing, neuroscience, light-controlled drug release and tissue imaging and diagnosis. In the optogenetics literature, there is a lack of standardized terminology for describing wavelength ranges of bacteriophytochrome (BphP)-based systems. These systems are generally sensitive to light within two wavelength ranges: 650-670 nm and 740-780 nm. Notably, the latter range is often described interchangeably as "far-red" or "near-infrared", terminology that is scientifically valid in both cases. To avoid ambiguity and maintain uniformity throughout this review, the designation "red/far-red" will be used exclusively when referring to these light-responsive systems.