Myocardial infarction (MI), a common and severe disease threatening human health worldwide, results from ischemic and hypoxic-induced necrosis of cardiac tissue due to coronary artery obstruction or rupture. Hydrogen sulfide (H₂S) is a gasotransmitter involved in various physiological and pathological processes. Exogenous supplementation of H₂S is significantly beneficial for the treatment of MI. In this study, a novel H₂S donor - zinc sulfide nanoparticles encapsulated in hyaluronic acid (HA@ZnS NPs), has been developed through a biomimetic mineralization process for the treatment of MI. HA@ZnS NPs can stably release H₂S at the site of myocardial ischemic injury due to the acidic microenvironment. Compared to the MI group, the NP-treated group significantly improved cardiac function, including increased left ventricular ejection fraction and fractional shortening, as well as reduced end-systolic volume. Furthermore, the NPs significantly reduced the size of the myocardial infarction area, improved left ventricular remodeling, and exerted therapeutic effects by promoting angiogenesis and reducing apoptosis in cardiac tissue. In conclusion, HA@ZnS NPs demonstrate potential for treating MI through precise control of H₂S release, providing valuable insights into new therapies for MI and laying the groundwork for the clinical application of H₂S-releasing materials in the future.

Depleting tumoral lactate is a promising strategy to enhance the immune response and thereby suppressing tumorigenesis. However, the direct use of lactate oxidase (LOx), the most straightforward lactate-eliminating agent, faces several issues including low stability, no targeting capacity. To solve these problems, a “carrier-free” nanodrug LOx@manganese sulfide (LOx@MnS) was facilely prepared via biomineralization. This way, all the constituents integrated in the nanodrug, including LOx, Mn2+, and hydrogen sulfide (H2S), could be readily delivered into tumor cells and exert their effects. LOx combined with Mn2+ to convert lactate to cytotoxic reactive oxygen species (ROS) through the cascade reaction, meanwhile the crosstalk between H2S and ROS induced metabolism suppression to further augment the therapeutic efficacy. Consequently, the multi-mode therapeutic modalities led to effective immune activation and tumor suppression, suggesting the great potential for tumor treatment. We believe this strategy opens a new avenue to construct functional materials from frangible biomolecules and expand their applications.

Hydrogen sulfide (H2S) plays crucial inflammatory modulating roles, representing a promising candidate for anti-inflammatory therapies. However, current H2S delivery approaches lack sufficient specificity against inflammatory response. Herein, regarding the overexpressed aminopeptidase N (APN) at the inflammation sites, an APN-activated self-immolative carbonyl sulfide (COS)/H2S donor (AlaCOS) was developed for inflammatory response-specific H2S delivery. The compound showed sustained H2S generation upon APN activation in the presence of carbonic anhydrase (CA), and the responsiveness could be well regulated by modulating the amino acid sequence. Due to the inflammatory response-specific sustained H2S delivery, AlaCOS provided potent anti-inflammatory capability, which was further validated by RNA sequencing. In vivo experiments on a full-thickness cutaneous wound murine model also showed the strong promoting effect on wound healing, mainly due to the regulation of the inflammatory response by AlaCOS. By introducing a caged coumarin fluorophore to the molecular architecture, self-reporting fluorescence could be generated accompanied with APN-mediated COS/H2S release, which achieved the visualization of H2S delivery in vitro and in vivo. This work not only offers a useful tool for studying the bioactivity of H2S on inflammation, but also provides new insights for developing novel therapies to cope with inflammation-associated diseases.

Gouty arthritis (GA) is a common arthritis characterized by abnormal deposition of monosodium urate (MSU) crystals in articular structures. Current clinical medications can only alleviate the inflammation caused by the acute GA temporarily, but have no solution to the deposition of MSU. To surmount this, urate oxidase (UOx) was initially modified with the phenylboronic acid-based self-immolative thiocarbamate through nucleophilic substitution, and then co-assembled with curcumin through boronate bond to form the platform (termed UBC). This way, the platform could not only directly eliminate the MSU, but also release the therapeutic gas hydrogen sulfide (H2S) triggered by the toxic by-product of UOx catalysis, hydrogen peroxide (H2O2). Synergized with curcumin, the inflammation could be effectively suppressed. In vivo experiments on an acute GA murine model also validated the potent therapeutic effect of the platform, mainly due to the synergistic effect of H2S and curcumin. We believe this strategy provides a novel approach for the treatment of inflammation-related diseases and novel insight into the construction of multi-functional therapeutic nanomaterials from enzymes and other biomolecules.

Nanomaterial-assisted chemodynamic cancer therapy has received considerable attention in recent years. It outperforms other modalities for its unique pattern of reactive oxygen species (ROS) production via the non-exogenous stimulant. However, the treatment outcome is limited by the insufficient content of endogenous hydrogen peroxide (H2O2). Herein, a biodegradable H2S-releasing MnS@HA-DOX nanocluster (MnS@HA-DOX NC) was constructed by in situ biomineralization from hyaluronic acid, to amplify ROS cascade and boost Mn2+-based chemodynamic therapy (CDT). The acid-responsive NCs could quickly degrade after internalization into endo/lysosomes, releasing Mn2+, H2S gas, and anticancer drug doxorubicin (DOX). The Fenton-like reaction catalyzed by Mn2+ was amplified by both H2S and DOX, producing a mass of cytotoxic ·OH radicals. Through the combined action of gas therapy (GT), CDT, and chemotherapy, oxidative stress would be synergistically amplified, inducing irreversible DNA damage and cell cycle arrest, eventually resulting in cancer cell apoptosis.

Diabetic ulcer receives much attention in recent years due to its high incidence and mortality, promoting the scientific community to develop various strategies for such chronic disease treatments. However, the therapeutic outcome of these approaches is highly compromised by the invasive bacteria and severe inflammatory ulcer microenvironment. To overcome these dilemmas, microenvironment-responsive self-delivery GOx@MnS nanoparticles (NPs) are developed by a one-step biomineralization. When encountered with high glucose level in the ulcer site, GOx catalyze glucose to decrease the local pH and trigger the steady release of both manganese ions (Mn2+) and hydrogen sulfide (H2S). Mn2+ react with hydrogen peroxide to generate hydroxyl radical for the elimination of bacterial infection, meanwhile H2S is able to suppress the inflammatory response and accelerate diabetic wound healing through macrophage polarization. The excellent biocompatibility, strong bactericidal activity, and considerable immunomodulatory effect promise GOx@MnS NPs great therapeutic potential for diabetic wound treatment.