Since the declaration of the COVID-19 pandemic by the World Health Organization on 11 March 2020, 1 COVID-19 has continued to spread worldwide. The causative pathogen is severe acute respiratory syndrome coronavirus 2, which spreads by airborne transmission and causes severe respiratory disease. 2 Given the ability of masks to prevent infection, 3 mask wear is now recommended in many countries and has become a necessity in daily life. However, various adverse skin reactions to masks have been recognized during the ongoing COVID-19 pandemic. Various mask-related skin disorders have been reported, including erythema, papules, pustules, acne mechanica and contact dermatitis. 4 Many people, including healthcare workers, who wear masks for long periods of time, experience skin reactions, such as rash, itching, dry skin and acne. 5-7 There is an increasing perception that masks affect the skin 8,9 and a growing interest in how mask-related skin damage can be avoided. A recent study found that short-term mask wear affects the characteristics of the skin, 10 and it is likely that these effects become more pronounced when a mask is worn for longer periods. To the best of our knowledge, there has been no study of the effect of longer-term mask wear on skin wrinkles and pores. Given the protracted nature of the

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Activation of Kupffer cells (KCs) by gut-derived lipopolysaccharide (LPS) instigates nuclear factor-κB (NF-κB)-mediated inflammatory responses in alcohol-associated liver diseases (ALD). Here, we utilized a novel optogenetically engineered exosome technology called ‘exosomes for protein loading via optically reversible protein–protein interactions (EXPLOR)’ to efficiently deliver the super-repressor IκB-loaded exosomes (Exo-srIκB) to the liver and examined its therapeutic potential in acute-on-chronic alcohol-associated liver injury. We detected enhanced uptake of DiI-labeled Exo-srIκB by LPS-treated inflammatory KCs, which suppressed LPS-induced inflammatory gene expression levels. In animal experiments, a single intravenous injection of Exo-srIκB prior to alcohol binge drinking significantly attenuated alcohol-associated hepatic steatosis and infiltration of neutrophils and macrophages but not a liver injury. Notably, three consecutive days of Exo-srIκB injection remarkably reduced alcohol-associated liver injury, steatosis, apoptosis of hepatocytes, fibrosis-related gene expression levels in hepatic stellate cells, infiltration of neutrophils and macrophages, and inflammatory gene expression levels in hepatocytes and KCs. In particular, the above effects occurred with inhibition of nuclear translocation of NF-κB in liver tissues, and these beneficial effects of Exo-srIκB on ALD were shown regardless of doses. Our results suggest an exosome-based modulation of NF-κB activity in KCs by Exo-srIκB as a novel and efficient therapeutic approach in ALD.