Reactive oxygen species-responsive nano-platform with dual-targeting and fluorescent lipid-specific imaging capabilities for the management of atherosclerotic plaques.

Atherosclerosis (AS), a pathological cause of cardiovascular disease, results from endothelial injury, local progressive inflammation, and excessive lipid accumulation. AS plaques rich in foam cells are prone to rupture and form thrombus, which can cause life-threatening complications. Therefore, the assessment of atherosclerotic plaque vulnerability and early intervention are crucial in reducing the mortality rates associated with cardiovascular disease. In this work, A fluorescent probe FC-TPA was synthesized, which switches the fluorescence state between protonated and non-protonated, reducing background fluorescence and enhancing imaging signal-to-noise ratio. On this basis, FC-TPA is loaded into cyclodextrin (CD) modified with phosphatidylserine targeting peptide (PTP) and coated with hyaluronic acid (HA) to construct the intelligent responsive diagnostic nanoplatform (HA@PCFT). HA@PCFT effectively targets atherosclerotic plaques, utilizing dual targeting mechanisms. HA binds strongly to CD44, while PTP binds to phosphatidylserine, enabling nanoparticle aggregation at the lesion site. ROS acts as a smart release switch for probes. Both in vitro and in vivo evaluations confirm impressive lipid-specific fluorescence imaging capabilities of HA@PCFT nanoparticles (NPs). The detection of lipid load in atherosclerotic plaque by fluorescence imaging will aid in assessing the vulnerability of atherosclerotic plaque. STATEMENT OF SIGNIFICANCE: Currently, numerous fluorescent probes have been developed for lipid imaging. However, some challenges including inadequate water solubility, nonspecific distribution patterns, and fluorescence background interference, have greatly limited their further applications in vivo. To overcome these limitations, a fluorescent molecule has been designed and synthesized, thoroughly investigating its photophysical properties through both theoretical and experimental approaches. Interestingly, this fluorescent molecule exhibits the reversible fluorescence switching capabilities, mediated by hydrogen bonds, which effectively mitigate background fluorescence interference. Additionally, the fluorescent molecules has been successfully loaded into nanocarriers functionalized with the active targeting abilities, which has significantly improved the solubility of the fluorescent molecules and reduced their nonspecific distribution in vivo for an efficient target imaging in atherosclerosis. This study provides a valuable reference for evaluating the performance of such fluorescent dyes, and offers a promising perspective on the design of the target delivery systems for atherosclerosis.

A Macrophage Membrane-Functionalized, Reactive Oxygen Species-Activatable Nanoprodrug to Alleviate Inflammation and Improve the Lipid Metabolism for Atherosclerosis Management.

Atherosclerosis (AS) management typically relies on therapeutic drug interventions, but these strategies typically have drawbacks, including poor site specificity, high systemic intake, and undesired side effects. The field of cell membrane camouflaged biomimetic nanomedicine offers the potential to address these challenges thanks to its ability to mimic the natural properties of cell membranes that enable enhanced biocompatibility, prolonged blood circulation, targeted drug delivery, and evasion of immune recognition, ultimately leading to improved therapeutic outcomes and reduced side effects. In this study, a novel biomimetic approach is developed to construct the M1 macrophage membrane-coated nanoprodrug (MM@CD-PBA-RVT) for AS management. The advanced MM@CD-PBA-RVT nanotherapeutics are proved to be effective in inhibiting macrophage phagocytosis and facilitating the cargo delivery to the activated endothelial cells of AS lesion both in vitro and in vivo. Over the 30-day period of nanotherapy, MM@CD-PBA-RVT is capable of significantly inhibiting the progression of AS, while also maintaining a favorable safety profile. In conclusion, the biomimetic MM@CD-PBA-RVT shows promise as feasible drug delivery systems for safe and effective anti-AS applications.

Nanogels with covalently bound and releasable trehalose for autophagy stimulation in atherosclerosis.

Atherosclerosis, cholesterol-driven plaque formation in arteries, is a complex multicellular disease which is a leading cause of vascular diseases. During the progression of atherosclerosis, the autophagic function is impaired, resulting in lipid accumulation-mediated foam cell formation. The stimulation of autophagy is crucial for the recovery of cellular recycling process. One of the potential autophagy inducers is trehalose, a naturally occurring non-reducing disaccharide. However, trehalose has poor bioavailability due to its hydrophilic nature which results in poor penetration through cell membranes. To enhance its bioavailability, we developed trehalose-releasing nanogels (TNG) for the treatment of atherosclerosis. The nanogels were fabricated through copolymerization of 6-O-acryloyl-trehalose with the selected acrylamide-type monomers affording a high trehalose conjugation (~ 58%, w/w). TNG showed a relatively small hydrodynamic diameter (dH, 67 nm) and a uniform spherical shape and were characterized by negative ζ potential (-18 mV). Thanks to the trehalose-rich content, TNG demonstrated excellent colloidal stability in biological media containing serum and were non-hemolytic to red blood cells. In vitro study confirmed that TNG could stimulate autophagy in foam cells and enhance lipid efflux and in vivo study in ApoE-/- mice indicated a significant reduction in atherosclerotic plaques, while increasing autophagic markers. In conclusion, TNG hold great promise as a trehalose delivery system to restore impaired autophagy-mediated lipid efflux in atherosclerosis and subsequently reduce atherosclerotic plaques.

Reactive Oxygen Species-Responsive Sequentially Targeted AIE Fluorescent Probe for Precisely Identifying the Atherosclerotic Plaques.

The formation of atherosclerosis is the root cause of various cardiovascular diseases (CVDs). Therefore, effective CVD interventions call for precise identification of the plaques to aid in clinical treatment of such diseases. Herein, a reactive oxygen species (ROS)-responsive sequentially targeted fluorescent probe is developed for atherosclerotic plaque recognition. An aggregation-induced emission active fluorophore is linked to maleimide (polyethylene glycol) hydroxyl with a ROS-responsive cleavable bond, which is further functionalized with CLIKKPF peptide (TPAMCF) for specifically binding to phosphatidylserine of the foam cells. After being assembled in aqueous medium, TPAMCF nanoparticles can efficiently accumulate in the plaques through the high affinity of CLIKKPF to the externalized phosphatidylserine of the foam cells. Activated by the locally accumulated ROS in foam cells, the nanoparticles are interrupted, and then TPA can be released and subsequently identify the lipid droplets inside the foam cells to achieve fluorescence imaging of the plaques. Such nanoprobes have the favorable ROS response performance and exhibit a special target binding to the foam cells in vitro. In addition, nanoprobe-based fluorescence imaging permitted the high-contrast and precise detection of atherosclerosis specimens ex vivo. Therefore, as a promising fluorescent probe, TPAMCF is capable of being a potential candidate for the detection of atherosclerotic plaque.

ROS responsive polydopamine nanoparticles to relieve oxidative stress and inflammation for ameliorating acute inflammatory bowel.

Oxidative stress is a key factor in the development of inflammatory diseases. Elimination of reactive oxygen species (ROS) in the inflamed colon has been confirmed as an effective strategy to alleviate inflammatory bowel disease (IBD). The conventional approaches will cause systemic absorption and potential side effects. To address these issues, we develop a nanomedicine (LS@PDA NPs) that is capable of delivering to target inflammatory lesions by electrostatic adsorption, subsequently effectively scavenging the excess ROS and alleviating inflammation to ameliorate ulcerative colitis (UC). In the DSS induced acute colitis mice model, LS@PDA NPs can significantly reduce the production of pro-inflammatory cytokines, alleviate oxidative stress, and promote the favorable recovery of the damaged colonic tissue. These results indicate that LS@PDA NPs are able to effectively alleviate intestinal inflammation and provide strong theoretical support for the treatment of other inflammatory diseases.

Cell membrane camouflaged biomimetic nanoparticles: Focusing on tumor theranostics.

Nanoparticles (NPs) modified by cell membranes represent an emerging biomimetic platform that can mimic the innate biological functions resulting from the various cell membranes in biological systems. researchers focus on constructing the cell membrane camouflaged NPs using a wide variety of cells, such as red blood cell membranes (RBC), macrophages and cancer cells. Cell membrane camouflaged NPs (CMNPs) inherit the composition of cell membranes, including specific receptors, antigens, proteins, for target delivering to the tumor, escaping immune from clearance, and prolonging the blood circulation time, etc. Combining cell membrane-derived biological functions and the NP cores acted cargo carriers to encapsulate the imaging agents, CMNPs are widely developed to apply in tumor imaging techniques, including computed tomography (CT), magnetic resonance imaging (MRI), fluorescence imaging (FL) and photoacoustic imaging (PA). Herein, in this review, we systematically summarize the superior functions of various CMNPs in tumor imaging, especially highlighting the advanced applications in different imaging techniques, which is to provide the theoretical supports for the development of precise guided imaging and tumor treatment.