Human umbilical cord mesenchymal stem cell-derived exosomes (hUC-MSC-Exos) are nanoscale vesicles (30-150 nm in diameter) with a lipid bilayer structure, serving as endogenous intercellular communication carriers. Their therapeutic potential in end-stage liver disease has been validated in multiple studies published in Stem Cell Research & Therapy.
The core advantages of hUC-MSC-Exos as therapeutic vectors lie in three aspects: First, they possess excellent biocompatibility and low immunogenicity due to their origin from mesenchymal stem cells, minimizing the risk of immune rejection during in vivo application. Second, their surface expresses specific molecules such as integrins and tetraspanins (e.g., CD63, CD81), which mediate targeted delivery to liver tissues by recognizing corresponding receptors on hepatocytes and hepatic stellate cells (HSCs). Third, the presence of CD47 on the exosome surface enables binding to signal regulatory protein α (SIRPα) on macrophages, inhibiting phagocytic clearance and prolonging their circulatory half-life in vivo.
Natural hUC-MSC-Exos have an inherent limitation of low therapeutic molecule content, which restricts their clinical efficacy. To address this bottleneck, hUC-MSCs are genetically engineered to construct and stably express fusion gene vectors, typically using lentiviral vectors or plasmid transfection techniques. This modification enhances the cellular synthesis of target effector molecules, ensuring that the secreted exosomes can efficiently co-load high concentrations of miR-455-3p and miR-148a-5p, thereby achieving optimized therapeutic effects.

miR-455-3p exerts anti-hepatic fibrosis effects primarily through regulating HSC metabolism and function. As an endogenous non-coding RNA, it modulates gene expression by specifically binding to the 3' untranslated region (3'UTR) of target mRNAs, inducing mRNA degradation or translational repression. A key mechanism involves the upregulation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a master regulator of mitochondrial biogenesis and energy metabolism. miR-455-3p potentially targets negative regulators of PGC-1α, indirectly increasing its expression. Elevated PGC-1α levels enhance mitochondrial oxidative phosphorylation capacity and promote mitochondrial autophagy (mitophagy) in activated HSCs, improving mitochondrial function and reducing reactive oxygen species (ROS) production. Impaired mitochondrial function is closely associated with HSC activation and extracellular matrix (ECM) synthesis. By restoring mitochondrial homeostasis, miR-455-3p inhibits HSC activation, reduces the expression of pro-fibrotic markers such as α-smooth muscle actin (α-SMA) and collagen type I, and decreases ECM deposition. Additionally, miR-455-3p participates in regulating the inflammatory microenvironment of the liver by enhancing the secretion of anti-inflammatory factors like interleukin-10 (IL-10), further contributing to anti-fibrotic effects.

The synergistic anti-liver fibrosis effect of miR-455-3p and miR-148a-5p stems from their complementary and coordinated regulation of multiple pathogenic links of liver fibrosis. Firstly, these two microRNAs act on different cellular processes in hepatic stellate cells respectively: miR-148a-5p mainly regulates the apoptosis of hepatic stellate cells and the TGF-β/Smad signaling pathway, while miR-455-3p focuses on metabolic reprogramming and mitochondrial function. This multi-target strategy ensures comprehensive inhibition of hepatic stellate cell activation from different angles, and has a stronger anti-fibrotic effect than single microRNA intervention. Secondly, they synergistically enhance the regulation of the inflammatory microenvironment. Both of these microRNAs can upregulate the secretion of anti-inflammatory factors such as IL-10, while possibly downregulating different pro-inflammatory mediators. This combined immunomodulatory effect more effectively alleviates the "inflammatory storm" in the liver and interrupts the mutual amplification of inflammation and fibrosis. Finally, the synergistic effect of miR-455-3p and miR-148a-5p may form a feedback loop to amplify the anti-fibrotic signal. For example, the metabolic improvement caused by miR-455-3p may enhance the sensitivity of hematopoietic stem cells to the apoptosis induced by miR-148a-5p, thereby further promoting the elimination of fibrosis. This synergistic mechanism enables the dual miRNA system to achieve a "1 + 1 > 2" therapeutic effect, providing a theoretical basis for the development of more effective and multi-targeted liver fibrosis treatment strategies.