A Transdermal Prion‐Bionics Supermolecule as a RAB3A Antagonist for Enhancing Facial Youthfulness

The mechanism research of skin wrinkles, conducted on volunteers underwent high-intensity desk work and mice subjected to partial sleep deprivation, revealed a significant reduction in dermal thickness associated with the presence of wrinkles. This can be attributed to the activation of facial nerves in a state of hysteria due to an abnormally elevated interaction between SNAP25 and RAB3A proteins involved in the synaptic vesicle cycle (SVC). Facilitated by AI-assisted structural design, a refined peptide called RSI_pep is developed to modulate this interaction and normalize SVC. Drawing inspiration from prions, which possess the ability to protect themselves against proteolysis and invade neighboring nerve cells through macropinocytosis, RSI_pep is engineered to demonstrate a GSH-responsive reversible self-assembly into a prion-like supermolecule (RSI_prion). RSI_prion showcases protease resistance, micropinocytosis-dependent cellular internalization, and low adhesion with constituent molecules in the cuticle, thereby endowing it with the transdermic absorption and subsequent biofunction in redressing the frenzied SVC. As a facial mud mask, it effectively reduces periorbital and perinasal wrinkles in the human face. Collectively, RSI_prion not only presents a clinical potential as an anti-wrinkle prion-like supermolecule, but also exemplifies a reproducible instance of bionic strategy-guided drug development that bestows transdermal ability upon the pharmaceutical molecule.