Secretome and Bioactive Molecules for the Enhancement of Aged Wound Healing

Skin ageing is a multidimensional process driven by the convergence of intrinsic biological changes and cumulative environmental stressors. These alterations progressively disrupt epidermal barrier integrity, compromise extracellular matrix (ECM) homeostasis, and establish a chronic low-grade inflammatory state that significantly impairs tissue repair. Consequently, aged skin represents a particularly vulnerable substrate for delayed or chronic wound healing, a condition that disproportionately affects elderly populations and imposes a substantial clinical and socioeconomic burden. This review delivers timely and integrative perspective on the molecular and cellular drivers of age-associated deficits in cutaneous wound repair and uncovers cell-free therapeutic strategies that may transform regenerative capacity in aged skin. Particular emphasis is placed on three interconnected therapeutic axes: (i) secretome-based approaches, including conditioned media, growth factors, cytokines and chemokines capable of modulating the wound microenvironment; (ii) extracellular vesicles (EVs), particularly those derived from mesenchymal stromal/stem cells and induced pluripotent stem cell (iPSC)-derived sources, with special attention to the role of miRNA cargo and intercellular communication functions; and (iii) miRNA-based interventions targeting key regenerative pathways. In addition, we discuss advanced delivery platforms, including stimuli-responsive hydrogels, nanofibrous scaffolds, particulate systems and microneedle arrays, that are specifically engineered to overcome the proteolytic instability, hypo-vascularization, and impaired cellular uptake characteristic of aged wounds. Collectively, this review highlights how secretome-derived therapies offer a scientifically robust and clinically viable approach for restoring regenerative competence in aged skin. By integrating molecular precision with innovative delivery engineering, these approaches hold considerable promise for transforming the management of chronic wounds associated with ageing.