LIFU-unlocked endogenous H₂S generation for enhancing atherosclerosis-specific gas-enzymatic therapy

Atherosclerotic plaques, which are characterized by endothelial oxidative stress, lipid metabolism disorders and persistent inflammation, can induce serious cardiovascular diseases. However, the pharmacotherapies currently used to treat atherosclerosis (AS), such as lipid-lowering and antithrombotic drugs, can regulate only a single pathological feature of AS, and there is still a dearth of integrated platforms for the multifaceted regulation of AS progression. Herein, we developed a synergistic combination of endogenous H₂S gas therapy with a multienzyme-like nanozyme (named ^LyP-1Lip@HS) for the treatment of AS. The high affinity of the LyP-1 peptide for macrophages and foam cells within plaques allows ^LyP-1Lip@HS to actively target atherosclerotic lesions. After cavitation was induced by low-intensity focused ultrasound (LIFU), the lipid membrane of ^LyP-1Lip@HS was disrupted, thereby "unlocking" the enzyme-like activity of hollow mesoporous Prussian blue (HMPB) and facilitating the release of the endogenous H₂S donor S-allyl-L-cysteine (SAC). Notably, H₂S endogenously generated by enzymatic catalysis plays multiple roles, upregulating the ATP-binding cassette transporter A1 in foam cells to increase lipid efflux and promote the conversion of M1 macrophages to M2 macrophages. Moreover, the high level of reactive oxygen species in the inflammatory microenvironment of the plaque was mitigated. Overall, ^LyP-1Lip@HS provides a specific and controlled treatment to prevent oxidative stress, inflammation and lipid metabolism disorders, making it a candidate for AS treatment.