Emerging therapeutic roles of small heat shock protein-derived mini-chaperones and their delivery strategies

The small heat shock protein (sHsp) family is a group of proteins in which some are induced in response to external stimuli, such as environmental and pathological stresses, while others are constitutively expressed. They show chaperone-like activity, protect cells from apoptosis, and maintain cytoskeletal architecture. Short sequences or fragments ranging from approximately 19-20 residues in sHsps were shown to display chaperone activity in vitro. These sequences are termed sHsp-derived mini-peptides/mini-chaperones. These peptides offer an advantage in providing protective and therapeutic effects over full-length proteins owing to their small molecular weight and easy uptake into the cells. Research on sHsp mini-chaperone therapy has recently received attention and advanced tremendously. sHsp mini-chaperones have shown a wide range of therapeutic effects, such as anti-aggregation of proteins, anti-apoptotic, anti-inflammatory, anti-oxidant, senolytic, and anti-platelet activity. The administration of mini-chaperones into the several disease animal models, including experimental autoimmune encephalomyelitis, cataract, age-related macular degeneration, glaucoma, and thrombosis through various routes reduced symptoms or prevented the progression of the disease. However, it was found that the therapeutic potential of sHsp mini-chaperones is limited by their short turnover and enzymatic degradation in circulation. Nonetheless, carrier molecules approach such as nanoparticles, cell penetration peptides, and extracellular vesicles increased their efficacy by enhancing the uptake, retention time, protection from enzymatic degradation, and site-specific delivery without altering their biological activity. In this context, this review highlights the recent advances in the therapeutic potential of sHsp-derived mini-chaperones, their effect in experimental animal models, and approaches for increasing their efficacy.