Title: Mesenchymal Stromal Cells Encapsulated in Immune-Modulating Gels: A Pathway to Reversing Fibrosis and Future Nano-Based Therapeutics

Abstract: Traditional antifibrotic therapies often struggle with patient adherence and limited efficacy, highlighting the need for advanced treatment strategies. Enhancing cell-based therapies for pulmonary fibrosis requires strategies that improve cellular retention and functions within target tissues after delivery. Single-cell encapsulation in gel coatings, designed with specific cues and immune checkpoint molecules, offers a promising strategy to formulate cell-based therapeutics for improved clinical outcomes. This approach aims to extend the residence time of encapsulated cells and modulate immune responses critical for effective tissue remodeling. Our study investigates the modification of soft alginate gel coatings around single mesenchymal stromal cells (MSCs) to minimize innate immune recognition, enabling them to modulate macrophage subpopulations in the lungs via paracrine mediators over an extended period. Our approach shows significant enhancements in resolving both transient and persistent lung fibrosis in experimental models.

Additionally, nano-based therapies, such as lipid-based nanoparticles like liposomes and biological nanoparticles naturally secreted by cells (extracellular vesicles, EVs), have emerged as promising, complex, biocompatible drug delivery systems. These advancements have attracted global attention among researchers, prompting rapid development of more effective drug delivery methods. The ideal nanoparticle safely transports its drug payload to a predetermined target, facilitating intracellular or extracellular release for direct internalization and desired therapeutic effects. Along the way, nanoparticles protect the drug from non-target tissues, prolonging circulation time and enabling sustained release. While encapsulated MSC therapy remains broad, nanovesicles functionalized with specific ligands offer a more precise approach.