Stem cell-derived extracellular vesicles in cancer theranostics: dual regulatory mechanisms, engineering strategies, and clinical translation

Stem cells, known for their exceptional self-renewal and multilineage differentiation capabilities, play critical roles in tumor initiation, progression, and therapeutic strategies. Extracellular vesicles (EVs) from non-malignant stem cells inherit specific biological traits from their parent cells, facilitating intercellular communication. In particular contexts, these EVs may demonstrate favorable biocompatibility, relatively low immunogenicity, and the ability to penetrate biological barriers and accumulate in tumor sites. This review, informed by a bibliometric analysis of 2,164 publications indexed in the Web of Science Core Collection, covers trends in annual publication output, citation dynamics, collaboration patterns among countries and institutions, keyword co-occurrence, thematic evolution, co-citation patterns, and the identification of key references. It offers an in-depth examination of the dual regulatory mechanisms enacted by native stem cell-derived EVs in cancer. The analysis categorizes these mechanisms into three functional themes: modulation of malignant phenotypes, chemosensitivity, and remodeling of the immune microenvironment, while emphasizing the role of the tumor microenvironment in reprogramming EVs toward pro-tumorigenic profiles. Concerning therapeutic strategies, the review details engineering approaches for cargo loading and surface functionalization that facilitate the encapsulation of chemotherapeutic agents, nucleic acids, functional proteins, and oncolytic viruses. It critically compares various modification methods, highlighting their potential in treating refractory tumors such as glioblastoma and pancreatic cancer. Additionally, the discussion includes emerging therapeutic applications, covering the reduction of chemoradiotherapy-induced toxicities, cancer vaccine development, synergistic combinations with conventional therapies, and imaging-integrated tumor visualization. Key translational barriers—such as production, quality control, heterogeneity, in vivo behavior, safety, and regulatory challenges—are scrutinized to facilitate clinical adoption. On the diagnostic front, leveraging the unique biological properties of cancer stem cells, the review systematically investigates the potential of CSC-derived EVs as liquid biopsy biomarkers, outlining their advantages over traditional protein markers and identifying translational gaps that hinder clinical implementation. Collectively, this review positions stem cell-derived EVs as next-generation theranostic tools in precision oncology, effectively linking therapeutic interventions (Sections 2–6) with diagnostic monitoring (Section 7) through a cohesive framework.