Atherosclerosis is a leading cause of vascular diseases worldwide. Whereas antioxidative therapy has been considered promising for the treatment of atherosclerosis in view of a critical role of reactive oxygen species (ROS) in the pathogenesis of atherosclerosis, currently available antioxidants showed considerably limited clinical outcomes. Herein, we hypothesize that a broad-spectrum ROS-scavenging nanoparticle can serve as an effective therapy for atherosclerosis, taking advantage of its antioxidative stress activity and targeting effects. As a proof of concept, a broad-spectrum ROS-eliminating material was synthesized by covalently conjugating a superoxide dismutase mimetic agent Tempol and a hydrogen-peroxide-eliminating compound of phenylboronic acid pinacol ester onto a cyclic polysaccharide β-cyclodextrin (abbreviated as TPCD). TPCD could be easily processed into a nanoparticle (TPCD NP). The obtained nanotherapy TPCD NP could be efficiently and rapidly internalized by macrophages and vascular smooth muscle cells (VSMCs). TPCD NPs significantly attenuated ROS-induced inflammation and cell apoptosis in macrophages, by eliminating overproduced intracellular ROS. Also, TPCD NPs effectively inhibited foam cell formation in macrophages and VSMCs by decreasing internalization of oxidized low-density lipoprotein. After intravenous (i.v.) administration, TPCD NPs accumulated in atherosclerotic lesions of apolipoprotein E-deficient (ApoE) mice by passive targeting through the dysfunctional endothelium and translocation via inflammatory cells. TPCD NPs significantly inhibited the development of atherosclerosis in ApoE mice after i.v. delivery. More importantly, therapy with TPCD NPs afforded stabilized plaques with less cholesterol crystals, a smaller necrotic core, thicker fibrous cap, and lower macrophages and matrix metalloproteinase-9, compared with those treated with control drugs previously developed for antiatherosclerosis. The therapeutic benefits of TPCD NPs mainly resulted from reduced systemic and local oxidative stress and inflammation as well as decreased inflammatory cell infiltration in atherosclerotic plaques. Preliminary in vivo tests implied that TPCD NPs were safe after long-term treatment via i.v. injection. Consequently, TPCD NPs can be developed as a potential antiatherosclerotic nanotherapy.

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Despite the great potential of numerous antioxidants for pharmacotherapy of diseases associated with inflammation and oxidative stress, many challenges remain for their clinical translation. Herein, a superoxidase dismutase/catalase‐mimetic material based on Tempol and phenylboronic acid pinacol ester simultaneously conjugated β‐cyclodextrin (abbreviated as TPCD), which is capable of eliminating a broad spectrum of reactive oxygen species (ROS), is reported. TPCD can be easily synthesized by sequentially conjugating two functional moieties onto a β‐cyclodextrin scaffold. The thus developed pharmacologically active material may be easily produced into antioxidant and anti‐inflammatory nanoparticles, with tunable size. TPCD nanoparticles (TPCD NP) effectively protect macrophages from oxidative stress‐induced apoptosis in vitro. Consistently, TPCD NP shows superior efficacies in three murine models of inflammatory diseases, with respect to attenuating inflammatory responses and mitigating oxidative stress. TPCD NP can also protect mice from drug‐induced organ toxicity. Besides the passive targeting effect, the broad spectrum ROS‐scavenging capability contributes to the therapeutic benefits of TPCD NP. Importantly, in vitro and in vivo preliminary experiments demonstrate the good safety profile of TPCD NP. Consequently, TPCD in its native and nanoparticle forms can be further developed as efficacious and safe therapies for treatment of inflammation and oxidative stress‐associated diseases.

To develop reactive oxygen species (ROS)-responsive anti-inflammatory materials and establish their structure–property correlations, a series of H2O2-eliminating materials (OxbCDs) were designed and synthesized by conjugating different phenylboronic acid pinacol ester (PBAP) groups onto a biocompatible scaffold compound β-cyclodextrin via varied linker groups. Both the H2O2-triggered hydrolysis profiles and H2O2-eliminating capacities of these materials were dependent on the chemical structure of the PBAP moieties. Together with the elucidation of hydrolysis mechanisms, we established structure–property correlations of these OxbCD materials. Extensive in vitro experiments revealed nanoparticles (NPs) based on OxbCDs showed no adverse biological effects on normal cells. OxbCD NPs could effectively inhibit inflammatory responses and oxidative stress in stimulated macrophages. Consistently, OxbCD NPs efficaciously alleviated the symptoms of peritonitis in mice, with respect to reducing the counts of neutrophils and macrophages as well as inhibiting the secretion of pro-inflammatory cytokines, chemokines, and oxidative mediators. Similarly, OxbCD NPs loaded with anti-inflammatory drugs displayed superior efficacy in an acute inflammation model of peritonitis in mice. More importantly, OxbCD NPs showed good biocompatibility after administration via different routes. Consequently, besides serving as anti-inflammatory materials, the newly developed H2O2-eliminating materials may be utilized as pharmacologically functional carriers for targeted therapy of many diseases associated with inflammation and oxidative stress.

A self-illuminating nanoparticle can function as an effective nanomedicine for inflammation imaging and cancer therapy.