Customized Proteinaceous Nanoformulation for In Vivo Chemical Reprogramming

Sweat gland (SwG) regeneration is crucial for the functional rehabilitation of burn patients. In vivo chemical reprogramming that harnessing the patient's own cells in damaged tissue is of substantial interest to regenerate organs endogenously by pharmacological manipulation, which could compensate for tissue loss in devastating diseases and injuries, for example, burns. However, achieving in vivo chemical reprogramming is challenging due to the low reprogramming efficiency and an unfavorable tissue environment. Herein, this work has developed a functionalized proteinaceous nanoformulation delivery system containing prefabricated epidermal growth factor structure for on‐demand delivery of a cocktail of seven SwG reprogramming components to the dermal site. Such a chemical reprogramming system can efficiently induce the conversion of epidermal keratinocytes into SwG myoepithelial cells, resulting in successful in situ regeneration of functional SwGs. Notably, in vivo chemical reprogramming of SwGs is achieved for the first time with an impressive efficiency of 30.6%, surpassing previously reported efficiencies. Overall, this proteinaceous nanoformulation provides a platform for coordinating the target delivery of multiple pharmacological agents and facilitating in vivo SwG reprogramming by chemicals. This advancement greatly improves the clinical accessibility of in vivo reprogramming and offers a non‐surgical, non‐viral, and cell‐free strategy for in situ SwG regeneration. This work has developed the functional proteinaceous nanoformulation for on‐demand co‐delivery of multiple pharmacological reprogramming factors, which selectively reprogram keratinocytes into myoepithelial cells and achieve de novo regeneration of functional sweat glands in vivo and in situ. This work shows the highest in vivo chemical reprogramming efficiency and offers a transgene‐free and clinically adaptable approach for burn treatment with improved rehabilitation.