Pulp–Dentin Regeneration via Cell Homing: Current Evidence and Perspectives on Cell-Free Regenerative Endodontic Therapy

<i>Background and Objectives</i>: The regeneration of the pulp-dentin complex represents an alternative to conventional root canal treatment, aiming to preserve tooth biology and function. Cell-free regenerative endodontic therapy (CF-RET) exploits endogenous stem cells from the periapical region without ex vivo cell manipulation. Despite growing interest, the biological mechanisms, clinical indications, and predictability of CF-RET remain not clearly defined. This structured narrative review aimed to update a previous review by analyzing recent human studies on CF-RET. <i>Materials and Methods</i>: This review was conducted using the PRISMA 2020 guidelines to guide transparent reporting of the literature search and study selection process and was registered in PROSPERO (CRD420251075131). In vitro and in vivo human studies published between January 2017 and December 2024 investigating CF-RET were included, while studies involving cell transplantation, non-human models, case reports, and reviews were excluded. Study selection, data extraction, and quality assessment using the QuADS tool were performed, and the evidence was synthesized using a qualitative narrative approach. <i>Results</i>: Sixty-four studies were included. In vitro studies reported favorable effects of growth factors, exosomes, and biomimetic scaffolds on stem cell viability, migration, proliferation, odontogenic differentiation, and angiogenesis, while neurogenic differentiation was less consistently investigated. Scaffold composition, microstructure, and rheological properties were also considered. In vivo studies mainly focused on immature teeth with incomplete root development and demonstrated positive clinical and radiographic outcomes, including root development and canal diameter reduction. <i>Conclusions</i>: The current evidence supports the biological potential of CF-RET as a regenerative approach; however, substantial heterogeneity, the limited number of clinical studies and the absence of standardized protocols preclude definitive conclusions, highlighting the need for further well-designed translational and clinical investigations considering clinical applicability.