Research progress and physical regulation prospects of mesenchymal stem cells and their exosomes in peripheral nerve injury repair

Peripheral nerve injury (PNI) often leads to long‑term motor, sensory and pain disorders. Traditional microscopic repair and autologous nerve transplantation can partially restore function and make it difficult to cope with long‑segment defects and complex injury scenarios. Although mesenchymal stem cell (MSC) transplantation has shown neurorepair potential in early studies, its clinical translation faces challenges such as tumorigenic risk, immune rejection, low cell survival rate, and standardization difficulties. Studies have demonstrated that the therapeutic effects of MSCs are mainly achieved through paracrine mechanisms rather than cell replacement, a finding that has promoted the development of cell‑free therapies. MSC‑derived exosomes (MSC‑Exos) are rich in key miRNAs such as miR‑21, miR‑146a, and miR‑126. They can promote axonal regeneration by activating the PI3K/Akt/mTOR signaling pathway, inhibit the NF‑κB pathway to reduce neuroinflammation, and induce M2 polarization of macrophages to improve the immune microenvironment. Thus, MSC‑Exos have become one of the most active research directions in biological therapy for peripheral nerve injury (PNI). On the other hand, physical therapies represented by electrical stimulation, ultrasound, light, and bioelectromagnetic fields are evolving from "rehabilitation methods" to "energy drugs" that directly regulate the neuroregenerative microenvironment and stem cell behavior, and can collaborate with biomaterials to construct multifunctional regulatory platforms. Based on a systematic review of recent advances in the cellular and molecular mechanisms, engineering strategies, and translational progress of MSCs and MSC‑Exos in promoting PNI repair, this article focuses on reviewing their synergistic effects with biomaterials and exogenous physical stimuli (electricity, magnetism, ultrasound, etc.), clarifies the scientific basis for the shift from cell replacement therapy to cell‑free exosome therapy, and accordingly prospects the potential application of new electromagnetic wavebands such as terahertz (THz) in MSC preconditioning and fine regulation of the microenvironment.