The need to understand the effects of mechanical loading on the microRNA cargo of mesenchymal stem/stromal cell-derived extracellular vesicles

The gap

Evidence profile

Sourced from the future work and stated challenges of the source papers, classified as general, spanning 3 journals.

Supporting evidence — 3 representative gaps

• Immunotherapies based on macrophage reprogramming in periodontitis and apical periodontitis (2026) · Clinical Oral Investigations · doi

  Macrophage reprogramming represents a paradigm shift in the adjunctive management of periodontal and periapi- cal diseases. However, key challenges remain. The devel- opment of orthotopic AP models for therapeutic intracanal delivery, along with the adoption of standardized evaluation criteria, is essential to strengthening the translational valid- ity of experimental findings. Optimizing the delivery systems is another priority. Although microparticles, extracellular vesicles (EVs), and local injections have shown efficacy, future platforms must ensure safety, specificity, and sustained controlled release within periodontal and periapical tissues. A deeper understanding of the molecular and cel- lular mechanisms underlying macrophage plasticity is also needed. Advanced technologies, such as single-cell sequencing and spatial transcriptomics, can provide pre- cise mapping of macrophage interactions with stromal and immune cells, as well as the metabolic pathways governing their polarization. Finally, scalability and clinical integration will determine real-world applicability. Cell-free therapies (e.g., MSC- derived exosomes or miRNA carriers) and cell-based inter- ventions require rigorous assessment of safety, feasibility, and cost-effectiveness. Their most significant potential lies in combination with conventional periodontal and endodon- tic procedures, where synergistic effects may achieve both inflammation resolution and functional regeneration. 1 3Clinical Oral Investigations (2026) 30:234 Conclusion This review highlights experimental preclinical approaches for treating periodontal and apical periodontitis (AP) by reprogramming macrophage polarization, underscoring their potential to transform regenerative endodontics and periodontology. A broad spectrum of strategies -including cytokines (CCL2, IL-37), inhibition of extracellular matrix proteins (FBLN3, Gremlin-1), functionalized biomateri- als, MSC-derived exosomes, regulatory miRNAs, pharma- cological agents (glipizide, apabetalone, DMOG, Stattic, azithromycin), and adoptive M2 macrophage transfer- have been shown to promote M2 polarization while suppress- ing M1-driven inflammation. These interventions converge on reducing bone loss, dampening destructive immune responses, and enhancing osteogenic and dental tissue regeneration. Collectively, both prophylactic and therapeutic mac- rophage-targeted therapies hold substantial promise as adjunctive strategies to conventional biofilm control for periodontitis and AP. Whether administered locally or sys- temically, these approaches require future studies to estab- lish standardized macrophage readouts, optimize delivery and dosing, and validate outcomes in orthotopic models to ensure successful clinical translation.

  generalfuture work
  Keywords: macrophage periodontal delivery cell polarization clinical reprogramming adjunctive orthotopic models therapeutic standardized experimental extracellular future
• MicroRNA signatures in inflammatory dental tissues: biomarkers and molecular mechanisms (2026) · Frontiers in Molecular Biosciences · doi

  shapes DPSC survival, angiogenesis and osteogenic/odontogenic differentiation. This framework clarifies why the same miRNA network may support host defense in one context but impair regeneration in another. ceRNA regenerative and miRNA-linked Pulpitis progression and repair are shaped by interacting signaling networks, immune, epigenetic and in which miRNAs circuits coordinate context-dependent responses. miRNA regulators for pulpitis therefore remain candidate and endodontic tissue repair (Palideh et al., 2023). For translation, extracellular vesicles (EVs) are being investigated as tools for diagnosis and therapeutic delivery because of their natural biocompatibility and capacity to carry regulatory nucleic acids (Andjus et al., 2020). therapeutic targets 7.1 Engineered vesicles and nanoframes for miRNA delivery the and the pulp cavity. Modifying through genetic engineering A central bottleneck for clinical translation is protecting fragile non-coding RNAs while achieving targeted, durable surface delivery within or contents of vesicles to develop engineered exosome therapies may enhance tissue- efficacy of noncoding RNA specific accumulation cargo, which could address stem immune including cell rejection (Saikia and Dhanushkodi, 2024). One proposed strategy uses mesenchymal stem cells that overexpress anti- inflammatory or differentiation-promoting miRNAs (such as miR-34a) to actively secrete exosomes enriched in the selected miRNA has been proposed as a potentially scalable drug delivery strategy (Vakhshiteh et al., 2021). limitations of direct low transplantation, survival and In addition to biogenic vectors, advances in nanochemistry have expanded options for direct miRNA delivery. For example, chemically modified, self-assembling DNA tetrahedral frameworks can load and deliver miRNAs, creating a highly stable, nuclease- resistant, and cell-penetrating nucleic acid nanocarrier platform for pulp regeneration (Wei et al., 2024). For complex dental defects, immobilization of exosomes derived from dental pulp stem cells onto inorganic biomaterials such as titanium scaffolds may enhance the biological activity of the material interface and accelerate the vascular remodeling and functional integration of local tissues (Zhang et al., 2024). For pulpitis, therapeutic feasibility will depend on local retention within the confined pulp cavity, protection from nuclease degradation, control of dose and release kinetics, and the avoidance of off-target immune activation. These challenges are especially important because vital-pulp therapy must preserve remaining healthy tissue while suppressing inflammation and supporting repair. 7.2 Cell-source expansion and microenvironmental preconditioning A two-axis framework helps organize miRNA functions in pulpitis: an immune-regulatory axis that controls inflammatory amplification and resolution, and a repair-competence axis that Scalable cell-free therapy requires a practical source of regenerative vesicles. The traditional view holds that only highly purified stem cell subpopulations can be used for regenerative therapy, but recent transcriptomic studies indicate that even

  generalfuture work
  Keywords: mirna delivery pulp cell pulpitis repair immune vesicles stem regenerative mirnas tissue therapeutic therapy axis
• Mechanical Loading Reshapes Mesenchymal Stem/Stromal Cell-Derived Extracellular Vesicle microRNA Cargo Toward Predicted Immunomodulatory and EV Cargo-Trafficking Pathways: An In Vitro Mechanobiology Study (2026) · Biomolecules · doi

  One challenge is the need to understand the effects of mechanical loading on the microRNA cargo of mesenchymal stem/stromal cell-derived extracellular vesicles. Another challenge is the requirement for a three-dimensional culture system that can mimic the in vivo environment. The study also faces the challenge of characterizing and isolating extracellular vesicles from conditioned media.

  generalstated challengesevidence 5/5
  Keywords: one challenge need understand effects mechanical loading microrna

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