Cell-penetrating peptides and ADSCs synergize to modulate ER stress, a translational platform for metabolic disorders

Endoplasmic reticulum (ER) stress is a critical factor in the onset and progression of various metabolic and inflammatory disorders, including insulin resistance, hepatic steatosis, and cardiovascular dysfunction. This stress triggers the unfolded protein response (UPR), which, through mediators like PERK, IRE1, and ATF6, initiates maladaptive pathways leading to inflammation, apoptosis, and cellular dysfunction. While targeted ER stress modulation is a promising therapeutic strategy, effective and precise delivery of modulatory agents to specific intracellular targets remains a significant challenge. This review explores a bioengineered approach to overcome this hurdle.

This review synthesizes recent advancements in bioengineering, focusing on the synergistic application of cell-penetrating peptides (CPPs) and adipose-derived stem cells (ADSCs) as a multifunctional therapeutic platform. It examines how CPPs facilitate the intracellular delivery of diverse therapeutic cargoes, such as siRNA, peptides, or small molecules, specifically targeting key ER stress mediators like CHOP, GRP78, IRE1, and NF-κB. Concurrently, the paper investigates the paracrine effects of ADSCs, highlighting their secretion of anti-inflammatory cytokines (e.g., IL-10), growth factors (e.g., VEGF, HGF, TGF-β), and antioxidants that actively regulate ER stress responses. The review integrates these two distinct yet complementary strategies to propose a comprehensive platform for modulating ER stress and its downstream pathological effects.

Cell-penetrating peptides (CPPs) are shown to effectively enable intracellular delivery of therapeutic agents, leading to the restoration of ER homeostasis, a reduction in inflammatory signaling, and improved cellular survival across diverse cell types, including hepatocytes, pancreatic β-cells, and cardiomyocytes. These targeted deliveries address specific ER stress pathways. Adipose tissue-derived stem cells (ADSCs) exert significant paracrine effects by secreting anti-inflammatory cytokines like IL-10, various growth factors such as VEGF, HGF, and TGF-β, and potent antioxidants. These secreted factors collectively regulate ER stress responses, contributing to tissue repair and metabolic homeostasis through adipogenic and endothelial differentiation. The observed downregulation of ER stress markers and mitigation of oxidative stress by ADSCs further enhance their therapeutic efficacy for metabolic disorders.

The synergistic combination of CPPs and ADSCs represents a robust, multifunctional therapeutic platform capable of precisely targeting ER stress and its complex downstream effects, offering a comprehensive approach to metabolic pathophysiology. This bioengineered synergy holds substantial translational potential for precision medicine.