Abstract
The rising burden of neurodegenerative diseases has exposed critical gaps in the development of diagnostic and therapeutic tools, particularly regarding their limited sensitivity, poor spatiotemporal resolution, and lack of treatment specificity. These shortcomings highlight the need for technologies that enable early disease detection, real-time monitoring of regenerative processes, and precise therapeutic interventions. This review focuses on recent advances in photonic biosensing and optogenetics, examining how these technologies are reshaping neural regeneration research and assessing their potential for clinical translation. Photonic biosensing platforms, including chemiluminescence, plasmonics, and fluorescencebased methods, now achieve ultrasensitive, multiplexed biomarker detection. These technologies can identify pathological biomarkers such as amyloid-beta, tau, and alphasynuclein at sub-picomolar concentrations, revealing molecular signatures years before symptom onset. Optogenetics provides unprecedented control over neural activity through light-sensitive proteins, offering millisecond temporal precision and cell-type specificity. Studies demonstrate that targeted optogenetic modulation can enhance synaptic plasticity, promote axonal regeneration, and restore functional connectivity. Preclinical models show memory restoration in Alzheimer's disease through hippocampal circuit reactivation, motor recovery in Parkinson's disease via basal ganglia stimulation, and movement restoration after spinal cord injury. Most notably, optogenetic therapy has achieved partial vision restoration in a blind patient with retinitis pigmentosa, marking a significant clinical milestone in humans. Three fundamental paradigm shifts characterize current progress in neural regeneration research. First, the field is transitioning from single-biomarker detection strategies to integrated multiparameter sensing platforms capable of simultaneously quantifying diverse molecular signatures, enabling a comprehensive assessment of disease states and regenerative processes. Second, static endpoint measurements are evolving toward dynamic real-time monitoring capabilities that capture temporal changes in cellular and molecular events during neural repair. Third, broad-spectrum pharmacological interventions are giving way to cell-type-specific neuromodulation strategies that selectively target distinct neuronal populations within affected circuits. Clinical translation faces substantial challenges that require systematic resolution. Biomarker standardization across diverse patient populations and validation through multicenter studies remain incomplete. Device miniaturization and optimization for chronic biocompatibility are essential for long-term implantation. Long-term safety assessments of optogenetic constructs, particularly regarding immune responses and potential genotoxicity, require rigorous clinical evaluation. Regulatory frameworks for these novel therapeutic modalities need further development. Despite these hurdles, continued technological innovation and interdisciplinary collaboration position photonic biosensing and optogenetics to deliver more precise diagnostic and therapeutic solutions for neurodegenerative diseases, potentially improving patient neurological outcomes and quality of life in the coming decade.