Biophysical regulation of cell plasticity for induced neuron generation

Biophysical signals are key regulators of development, tissue regeneration, aging, disease pathogenesis, and cellular plasticity, yet they have received considerably less attention than biochemical cues. Defined as the capacity of cells to alter their phenotypes in response to diverse stimuli, cell plasticity has become a cornerstone of regenerative medicine, disease modeling, and pharmaceutical research. However, the robust epigenetic barriers in mature cells severely hamper cell fate conversion, and overreliance on biochemical inducers often triggers cytotoxic side effects. During development, biophysical signals can activate specialized mechanotransduction programs, which interact dynamically with biochemical signals to modulate cell fate. Cumulative studies have shown that external biophysical cues, whether used individually or in combination with chemical regulators, markedly enhance cell transition efficiency. Integrating physical and biochemical cues therefore provides a powerful paradigm for accurate cell-fate manipulation. In this review, we comprehensively summarize four mainstream biophysical strategies for generating induced neurons (iNs) in vitro: matrix stiffness/viscoelasticity, matrix topography, mechanically induced cell deformation, and non-contact physical stimulation. We further dissect the underlying mechanisms linking mechanosensitive proteins, canonical mechanotransduction pathways, and epigenetic remodeling. Overall, biophysical cue-guided cell fate conversion represents a promising strategy for generating functional neurons and other cell types, with potential applications in disease modeling, regenerative medicine, and cell-based therapies. Cell plasticity is an evolutionarily conserved biological trait, offering promising therapeutic potential for neurodegenerative diseases and neural injuries. Biophysical cues serve as powerful regulators of cell fate, acting via distinct mechanotransduction and epigenetic pathways. Combined biophysical and biochemical strategies markedly improve the efficiency and quality of induced neuron generation. Systematic screening and optimization of biophysical cues facilitate the development of novel therapeutic approaches for neurological disorders.