The generation and delivery techniques of cold atmospheric plasma (CAP), coupled with their innovative applications in treating various diseases, have given rise to plasma medicine as a novel therapeutic modality, offering new approaches for managing chronic diseases. CAP therapy generates a large number of reactive species that selectively modulate biological activities, yielding long-lasting effects and minimizing the risk of drug resistance, which is challenging to achieve with small molecule drugs. However, before CAP can be effectively utilized in chronic disease treatment, numerous limitations must be addressed. This review comprehensively summarizes the latest research progress in CAP-based chronic disease treatments, with a focus on the main CAP generation devices, delivery methods, and therapeutic mechanisms. Additionally, it addresses the key scientific issues in the development of plasma medicine, aiming to optimize therapeutic outcomes and provide a robust theoretical foundation and guiding principles for the effective clinical implementation of CAP.

Androgenetic alopecia (AGA) is a chronic and progressive form of hair loss characterized by vascular degeneration in the perifollicular microenvironment, leading to cell apoptosis and eventual loss of hair follicles (HFs). Traditional therapeutic formulations, such as Minoxidil (MXD) tincture, have limitations in reshaping the perifollicular microenvironment and exhibit limited effectiveness. Here, we report a multi-synergistic therapeutic platform for high-performance hair regeneration therapy. The platform combines microneedle (MN) patches loaded with MXD-encapsulated nanostructured lipid carriers (MXD-NLC-MNs) and cold atmospheric plasma (CAP). The MNs’ mechanical strength enables efficient transdermal delivery of MXD to the targeted dermal papilla cells, promoting cell proliferation. Furthermore, in collaboration with MXD, the mechanical stimulation exerted by MN application synergistically upregulates the expression of vascular endothelial growth factor, leading to neoangiogenesis. Meanwhile, the transient microchannels in the skin created by MNs facilitate the transdermal delivery of CAP-generated nitric oxide (NO) to the sites of HF lesions, whereby the synergistic interaction between MXD and NO boosts perifollicular vasodilation. Consequently, the perifollicular microenvironment can be effectively reshaped to accelerate hair regeneration in AGA murine models. This multi-synergistic combination therapy strategy would hold great promise for effectively treating AGA and promoting hair regrowth.