MSC secretomes as a cell-free therapeutic platform: Molecular heterogeneity, disease-specific bioactivity, delivery strategies, and regulatory translation across six major disease areas.

The mesenchymal stromal/stem cell (MSC) secretome is emerging as a cell-free pharmacological agent with multitarget activity in regenerative and inflammatory diseases. Rather than durable engraftment or differentiation, most therapeutic effects of MSC-based therapies are mediated by a complex mixture of soluble factors and extracellular vesicles (EVs) that can, in principle, be formulated as standardized biological drugs. This review appraises current evidence on MSC secretome composition, mechanisms of action, and pharmacological profile, emphasizing its potential as a scalable off-the-shelf platform. We first characterize the source-dependent architecture of the MSC secretome derived from bone marrow, adipose tissue, and umbilical cord, identifying a conserved core of 894 shared proteins alongside tissue-specific signatures that determine differential bioactivity. Pharmacologically active components are classified by mechanism, encompassing anti-inflammatory, pro-angiogenic, neuroprotective, antifibrotic, and regenerative mediators. We then critically examine preclinical evidence for secretome- and EV-based interventions across cardiovascular, neurological, ocular, inflammatory, musculoskeletal, and dermatological diseases, comparing mechanistic profiles, delivery routes, and potential advantages over current standard-of-care therapies. Finally, we address key translational challenges, including conditioning strategies to modulate secretome potency, biomaterial-assisted encapsulation and controlled-release technologies to improve stability and bioavailability, and the European regulatory framework, in which MSC secretome products are classified as biological medicinal products rather than Advanced Therapy Medicinal Products (ATMPs), with implications for Good Manufacturing Practice (GMP)-compliant production. We propose a research agenda centered on multiparametric potency assays linked to defined mechanisms of action, predictive pharmacokinetic/pharmacodynamic (PK/PD) biomarkers, rational combination with conventional therapies, and adaptive clinical trial designs aligned with regulatory expectations for complex biologics. Overall, MSC secretomes represent a promising class of cell-free pharmacological agents whose clinical implementation will depend on integrated drug-development strategies that combine pharmacology, biomaterials engineering, manufacturing science, and regulatory science.