Advances in vesicular nanocarrier-mediated therapies for hypertrophic scars: mechanistic insights, preclinical evidence and clinical perspectives.

Hypertrophic scars (HSs) remain a significant clinical challenge, as prevention is difficult and current treatments often yield limited outcomes. The dense fibrotic architecture of established scar tissue, along with the invasiveness, limited patient acceptability, and high cost of intralesional and laser-based therapies, further restricts treatment success. In recent years, vesicular nanocarriers have gained increasing attention as advanced systems for enhancing dermal drug penetration and modulating key molecular pathways involved in pathological scarring. This review summarizes the biological differences between normal wound healing and HS formation, emphasizing the cellular and molecular signaling pathways responsible for excessive fibrosis. A particular focus is placed on the mechanistic explanation of how certain vesicular nanocarriers penetrate scar tissue lacking skin appendages via intracellular and intercellular routes, whereas others require combination with physical delivery methods due to their physicochemical characteristics. Major vesicular systems, including liposomes, transfersomes, ethosomes, niosomes, and exosomes, are discussed regarding their composition, skin penetration mechanisms, and preclinical evidence supporting their potential in HS prevention and treatment. Early-stage clinical studies are highlighted to evaluate translational prospects. Furthermore, regulatory considerations related to manufacturing, quality control, and clinical application are addressed. Finally, the review discusses current challenges and future perspectives to guide the rational design and clinical translation of vesicular nanocarrier-based therapies for improved HS management.