Biomimetic Nano-Degrader Based CD47-SIRPα Immune Checkpoint Inhibition Promotes Macrophage Efferocytosis for Cardiac Repair.

CD47-SIRPα axis is an immunotherapeutic target in tumor therapy. However, current monoclonal antibody targeting CD47-SIRPα axis is associated with on-target off-tumor and antigen sink effects, which significantly limit its potential clinical application. Herein, a biomimetic nano-degrader is developed to inhibit CD47-SIRPα axis in a site-specific manner through SIRPα degradation, and its efficacy in acute myocardial infarction (AMI) is evaluated. The nano-degrader is constructed by hybridizing liposome with red blood cell (RBC) membrane (RLP), which mimics the CD47 density of senescent RBCs and possesses a natural high-affinity binding capability to SIRPα on macrophages without signaling capacity. RLP would bind with SIRPα and induce its lysosomal degradation through receptor-mediated endocytosis. To enhance its tissue specificity, Ly6G antibody conjugation (aRLP) is applied, enabling its attachment to neutrophils and accumulation within inflammatory sites. In the myocardial infarction model, aRLP accumulated in the infarcted myocardium blocks CD47-SIRPα axis and subsequently promoted the efferocytosis of apoptotic cardiomyocytes by macrophage, improved heart repair. This nano-degrader efficiently degraded SIRPα in lysosomes, providing a new strategy for immunotherapy with great clinical transformation potential.

Genetically Engineered Macrophages Co-Loaded with CD47 Inhibitors Synergistically Reconstruct Efferocytosis and Improve Cardiac Remodeling Post Myocardial Ischemia Reperfusion Injury.

Efferocytosis, mediated by the macrophage receptor MerTK (myeloid-epithelial-reproductive tyrosine kinase), is a significant contributor to cardiac repair after myocardial ischemia-reperfusion (MI/R) injury. However, the death of resident cardiac macrophages (main effector cells), inactivation of MerTK （main effector receptor), and overexpression of "do not eat me" signals (brake signals, such as CD47), collectively lead to the impediment of efferocytosis in the post-MI/R heart. To date, therapeutic strategies targeting individual above obstacles are relatively lacking, let alone their effectiveness being limited due to constraints from the other concurrent two. Herein, inspired by the application research of chimeric antigen receptor macrophages (CAR-Ms) in solid tumors, a genetically modified macrophage-based synergistic drug delivery strategy that effectively challenging the three major barriers in an integrated manner is developed. This strategy involves the overexpression of exogenous macrophages with CCR2 (C-C chemokine receptor type 2) and cleavage-resistant MerTK, as well as surface clicking with liposomal PEP-20 (a CD47 antagonist). In MI/R mice model, this synergistic strategy can effectively restore cardiac efferocytosis after intravenous injection, thereby alleviating the inflammatory response, ultimately preserving cardiac function. This therapy focuses on inhibiting the initiation and promoting active resolution of inflammation, providing new insights for immune-regulatory therapy.

The Peripandemic Impact of the First Wave of the COVID-19 Pandemic on Management and Prognosis of ST-Segment Elevation Myocardial Infarction in China.

BACKGROUND: Rapid reperfusion of ST-segment elevation myocardial infarction (STEMI) has been challenging during the coronavirus disease 2019 (COVID-19) outbreak. Whether and to what degree there will be a residual impact when the COVID-19 pandemic has passed is unclear. METHODS: This nationwide retrospective study was based on electronic records of STEMI patients registered in the Chinese Cardiovascular Association Database. RESULTS: We analyzed 141,375 STEMI patients (including 4871 patients in Hubei province, where 80% of COVID-19 cases in China occurred in 2019-2020) during the pre-outbreak (23 October 2019-22 January 2020), outbreak (23 January 2020-22 April 2020), and post-outbreak (23 April 2020-22 July 2020) periods. In the post-outbreak period in Hubei province, the increased in-hospital mortality dropped to become insignificant (adjusted odds ratio compared to the pre-outbreak level (aOR) 1.40, [95% confidential interval (CI): 0.97-2.03]) and was lower than that in the outbreak period (1.62 [1.09-2.41]). The decreased odds of primary percutaneous coronary intervention (PCI) (0.73 [0.55-0.96]) and timely reperfusion (0.74 [0.62-0.88]) persisted, although they were substantially improved compared to the outbreak period (aOR of primary PCI: 0.23 [0.18-0.30] and timely reperfusion: 0.43 [0.35-0.53]). The residual impact of COVID-19 on STEMI in the post-outbreak period in non-Hubei provinces was insignificant. CONCLUSIONS: Residual pandemic impacts on STEMI management persisted after the first wave of the COVID-19 outbreak in Hubei province, the earliest and hardest hit area in China.

Targeted delivery and ROS-responsive release of Resolvin D1 by platelet chimeric liposome ameliorates myocardial ischemia-reperfusion injury.

Resolvin D1 (RvD1) has been shown to provide effective protection against ischemia-reperfusion injury in multiple vital organs such as the heart, brain, kidney. However, the clinical translational potential of systemic administration of RvD1 in the treatment of ischemia-reperfusion injury is greatly limited due to biological instability and lack of targeting ability. Combining the natural inflammatory response and reactive oxygen species (ROS) overproduction after reperfusion injury, we developed a platelet-bionic, ROS-responsive RvD1 delivery platform. The resulting formulation enables targeted delivery of RvD1 to the injury site by hijacking circulating chemotactic monocytes, while achieving locally controlled release. In a mouse model of myocardial ischemia repefusuin (MI/R) injury, intravenous injection of our formula resulted in the enrichment of RvD1 in the injured area, which in turn promotes clearance of dead cells, production of specialized proresolving mediators (SPMs), and angiogenesis during injury repair, effectively improving cardiac function. This delivery system integrates drug bio-protection, targeted delivery and controlled release, which endow it with great clinical translational value.

Targeted neutrophil-mimetic liposomes promote cardiac repair by adsorbing proinflammatory cytokines and regulating the immune microenvironment.

Acute myocardial infarction (MI) induces a sterile inflammatory response that may result in poor cardiac remodeling and dysfunction. Despite the progress in anti-cytokine biologics, anti-inflammation therapy of MI remains unsatisfactory, due largely to the lack of targeting and the complexity of cytokine interactions. Based on the nature of inflammatory chemotaxis and the cytokine-binding properties of neutrophils, we fabricated biomimetic nanoparticles for targeted and broad-spectrum anti-inflammation therapy of MI. By fusing neutrophil membranes with conventional liposomes, we fabricated biomimetic liposomes (Neu-LPs) that inherited the surface antigens of the source cells, making them ideal decoys of neutrophil-targeted biological molecules. Based on their abundant chemokine and cytokine membrane receptors, Neu-LPs targeted infarcted hearts, neutralized proinflammatory cytokines, and thus suppressed intense inflammation and regulated the immune microenvironment. Consequently, Neu-LPs showed significant therapeutic efficacy by providing cardiac protection and promoting angiogenesis in a mouse model of myocardial ischemia-reperfusion. Therefore, Neu-LPs have high clinical translation potential and could be developed as an anti-inflammatory agent to remove broad-spectrum inflammatory cytokines during MI and other neutrophil-involved diseases.

Targeted immunomodulation therapy for cardiac repair by platelet membrane engineering extracellular vesicles via hitching peripheral monocytes.

Immune regulation therapies have been considered promising in the treatment of myocardial ischemia reperfusion (MI/R) injury. Mesenchymal stem cells derived extracellular vesicles (MSC-EVs) are of great potential for immune modulation by reprogramming macrophages but their therapeutic efficacy is hindered by insufficient targeting ability in vivo. Herein, we introduced the platelet membrane modified EVs (P-EVs) based on membrane fusion method to mimic the binding ability of platelets to monocytes. In the mouse model of MI/R injury, the intravenously injected P-EVs were mainly carried by circulating monocytes into the ischemic myocardium. In the inflammatory microenvironment, those monocytes subsequently differentiated into macrophages with enhanced phagocytosis, which probably promoted in-situ endocytosis of the superficial P-EVs by monocytes differentiated macrophages in large quantities. Then, the P-EVs successfully escaped from the macrophage lysosome and released the functional microRNAs (miRNAs) into the cytosol which facilitated the inflammatory macrophages (M1 phenotype) reprogramming to reparative macrophages (M2 phenotype). Finally, the immune microenvironment was regulated to realize cardiac repair. Thus, we supposed that the most likely delivery method was that monocytes mediated P-EVs migration into ischemic myocardium where P-EVs were mainly in-situ endocytosed by monocytes derived macrophages, which holds potential for immunoregulation on MI/R and other immune-related diseases in the future.

Platelet-Like Fusogenic Liposome-Mediated Targeting Delivery of miR-21 Improves Myocardial Remodeling by Reprogramming Macrophages Post Myocardial Ischemia-Reperfusion Injury.

Inflammatory modulations focusing on macrophage phenotype are promising candidates to promote better cardiac healing post myocardial ischemia-reperfusion (MI/R) injury. However, the peak of monocyte/macrophage recruitment is later than the time when enhanced permeability and retention effect disappears, which greatly increases the difficulty of reprogramming macrophages through systemic administration. Meanwhile, the inability of nanomaterials to release their contents to specific intracellular locations through reasonable cellular internalization pathways is another obstacle to achieving macrophage reprogramming. Here, inspired by the increase in circulating platelet-monocyte aggregates in patients' post-MI/R and the high efficiency of fusogenic liposomes to deliver contents to the cytoplasm of target cells, a platelet-like fusogenic liposome (PLPs) is constructed. Under the coating of PLPs, mesoporous silica nanospheres with a payload of miR-21, an anti-inflammatory agent, can be specifically delivered to inflammatory monocytes in the blood circulation of MI/R induced mice. Then it directly enters the cytoplasm of monocytes through membrane fusion, thereby realizing the reparative reprogramming of the inflamed macrophages derived from it. In vivo administration of the resulting formula can effectively preserve the cardiac function of mice undergone MI/R. Minimal invasiveness and biological safety make this nano-platform a promising approach of immunotherapy.

Double kissing inflation outside the stent secures the patency of small side branch without rewiring.

BACKGROUND: The jailed balloon technique is widely used for coronary bifurcation lesions, but a residual risk of SB occlusion remains, necessitating SB rewiring and further interventions, including balloon inflation or stenting, which may result in failure and SB loss. This study introduced a novel modified technique of small side branch (SB) protection, namely, double kissing inflation outside the stent (DKo) technique, for coronary bifurcations without the need for SB rewiring. METHODS: We performed the DKo technique in consecutive patients in our center from 1/2019 to 12/2019. The procedure was as follows. We inserted a guide wire into both branches followed by proper preparation. The SB balloon was simultaneously inflated with main vessel (MV) stenting. The SB balloon remained in situ until it was kissing inflated with postdilation of the bifurcation core, which is different from traditional strategies. The proximal optimization technique was performed with a short noncompliant balloon strictly not exceeding the bifurcation. Rates of SB loss and in-hospital outcomes were evaluated. RESULTS: The technique was successfully performed in all 117 enrolled patients without any rewiring or SB loss. The mean lesion lengths of the MV and SB were 38.3 ± 19.9 mm and 11.7 ± 7.1 mm, respectively. On average, 1.5 ± 0.6 stents were used per patient, while the mean pressure of the SB balloon was 7.4 ± 3.1 atm. DKo achieved excellent procedural success in the proximal and distal MVs: increased minimal lumen diameter (0.64 ± 0.58 mm to 3.05 ± 0.38 mm, p < 0.001; 0.57 ± 0.63 mm to 2.67 ± 0.35 mm, p < 0.001) and low residual stenosis (11.4 ± 3.4%; 7.2 ± 4.6%). DKo secured the patency of the SB without any rewiring and improved the SB stenosis with minimal lumen diameter (0.59 ± 0.48 mm to 1.20 ± 0.42 mm, p < 0.001) and stenosis (71.9 ± 19.4% to 42.2 ± 14.0%, p < 0.001). No MACE was noted in the hospital. CONCLUSIONS: DKo for bifurcation lesions was shown to be acceptable with high procedural success and excellent SB protection.