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A principal goal of cancer nanomedicine is to deliver therapeutics effectively to cancer cells within solid tumors. However, there are a series of biological barriers that impede nanomedicine from reaching target cells. Here, we report a stimuli-responsive clustered nanoparticle to systematically overcome these multiple barriers by sequentially responding to the endogenous attributes of the tumor microenvironment. The smart polymeric clustered nanoparticle (iCluster) has an initial size of ∼100 nm, which is favorable for long blood circulation and high propensity of extravasation through tumor vascular fenestrations. Once iCluster accumulates at tumor sites, the intrinsic tumor extracellular acidity would trigger the discharge of platinum prodrug-conjugated poly(amidoamine) dendrimers (diameter ∼5 nm). Such a structural alteration greatly facilitates tumor penetration and cell internalization of the therapeutics. The internalized dendrimer prodrugs are further reduced intracellularly to release cisplatin to kill cancer cells. The superior in vivo antitumor activities of iCluster are validated in varying intractable tumor models including poorly permeable pancreatic cancer, drug-resistant cancer, and metastatic cancer, demonstrating its versatility and broad applicability.

Modulating effector immune cells via monoclonal antibodies (mAbs) and facilitating the co-engagement of T cells and tumor cells via chimeric antigen receptor- T cells or bispecific T cell-engaging antibodies are two typical cancer immunotherapy approaches. We speculated that immobilizing two types of mAbs against effector cells and tumor cells on a single nanoparticle could integrate the functions of these two approaches, as the engineered formulation (immunomodulating nano-adaptor, imNA) could potentially associate with both cells and bridge them together like an ‘adaptor’ while maintaining the immunomodulatory properties of the parental mAbs. However, existing mAbs-immobilization strategies mainly rely on a chemical reaction, a process that is rough and difficult to control. Here, we build up a versatile antibody immobilization platform by conjugating anti-IgG (Fc specific) antibody (αFc) onto the nanoparticle surface (αFc-NP), and confirm that αFc-NP could conveniently and efficiently immobilize two types of mAbs through Fc-specific noncovalent interactions to form imNAs. Finally, we validate the superiority of imNAs over the mixture of parental mAbs in T cell-, natural killer cell- and macrophage-mediated antitumor immune responses in multiple murine tumor models. Current strategies to boost anti-tumor immune response include the use of immune checkpoint inhibitors and bispecific T cell-engaging antibodies. Here the authors describe a versatile antibody immobilization nanoplatform that can be used to deliver different combinations of immunotherapeutics, showing therapeutic superiority in pre-clinical models.

Muscle genetic defects can lead to impaired movement, respiratory failure, and other severe symptoms. The development of curative therapies is challenging due to the need for the delivery of gene-editing tools into skeletal muscle cells throughout the body. Here, we use muscular fusogens (Myomaker and Myomerger) to engineer muscle-specific virus-like particles (MuVLPs) for the systemic delivery of gene-editing tools. We demonstrate that MuVLPs can be loaded with diverse payloads, including EGFP, Cre and Cas9/sgRNA ribonucleoproteins (Cas9 RNPs), and can be delivered into skeletal muscle cells via targeted membrane fusion. Systemic administration of MuVLPs carrying Cas9 RNPs enables skeletal muscle-specific gene editing, which excised the exon containing a premature terminator codon mutation in a mouse model for Duchenne muscular dystrophy (DMD). This treatment restores dystrophin expression in various skeletal muscle tissues, including the diaphragm, quadriceps, tibialis anterior, gastrocnemius, and triceps. As a result, the treated mice exhibit a significantly increased capacity for exercise and endurance. This study established a platform for precise gene editing in skeletal muscle tissues. Genetic muscle diseases are difficult to treat due to challenges in delivering gene editors to muscles throughout the body. Here, authors engineer muscle-specific virus-like particles that fuse with skeletal muscle cells to deliver CRISPR tools and restore dystrophin in a DMD model.

Background Hemodialysis patients are prone to gastrointestinal bleeding, and Mallory-Weiss syndrome (MWS) is one of the causes. Mallory-Weiss syndrome is often induced by severe vomiting, manifests as upper gastrointestinal bleeding, and is self-limited with a good prognosis. However, mild vomiting in hemodialysis patients can lead to the occurrence of MWS, and the mild early symptoms are easy to misdiagnose, leading to the aggravation of the disease. Case presentation In this paper, we report four hemodialysis patients with MWS. All patients displayed symptoms of upper gastrointestinal bleeding. The diagnosis of MWS was confirmed by gastroscopy. One patient had a history of severe vomiting; however, the other three reported histories of mild vomiting. Three patients received the conservative hemostasis treatment, and the gastrointestinal bleeding stopped. One patient underwent the gastroscopic and interventional hemostasis treatments. The conditions of three of the patients improved. Unfortunately, one of the patients died due to the cardia insufficiency. Conclusions We think that the mild symptoms of MWS are easily covered up by other symptoms. This may lead to delays in diagnosis and treatment. For patients with severe symptoms, gastroscopic hemostasis is still the first choice, and interventional hemostasis can also be considered. For patients with mild symptoms, drug hemostasis is the first consideration.

Although the phosphodiesterase type 5 inhibitors sildenafil and tadalafil have demonstrated efficacy in patients with pulmonary arterial hypertension (PAH), monotherapy with these agents has not been conclusively shown to reduce clinical worsening events. To evaluate the safety and efficacy of the phosphodiesterase type 5 inhibitor vardenafil in Chinese patients with PAH. In a randomized, double-blind, placebo-controlled study, 66 patients with PAH were randomized 2:1 to vardenafil (5 mg once daily for 4 wk then 5 mg twice daily; n = 44) or placebo (n = 22) for 12 weeks. Patients completing this phase were then treated with open-label vardenafil (5 mg twice daily) for a further 12 weeks. At Week 12, the mean placebo-corrected 6-minute walking distance was increased with vardenafil (69 m; P < 0.001), and this improvement was maintained for at least 24 weeks. Vardenafil also increased the mean placebo-corrected cardiac index (0.39 L·min(-1)·m(-2); P = 0.005) and decreased mean pulmonary arterial pressure and pulmonary vascular resistance (-5.3 mm Hg, P = 0.047; -4.7 Wood U, P = 0.003; respectively) at Week 12. Four patients in the placebo group (20%) and one in the vardenafil group (2.3%) had clinical worsening events (hazard ratio 0.105; 95% confidence interval, 0.012-0.938; P = 0.044). Vardenafil was associated with only mild and transient adverse events. Vardenafil is effective and well tolerated in patients with PAH at a dose of 5 mg twice daily.

The KRAS mutation is present in ∼20% of lung cancers and has not yet been effectively targeted for therapy. This mutation is associated with a poor prognosis in non-small-cell lung carcinomas (NSCLCs) and confers resistance to standard anticancer treatment drugs, including epidermal growth factor receptor tyrosine kinase inhibitors. In this study, we exploited a new therapeutic strategy based on the synthetic lethal interaction between cyclin-dependent kinase 4 (CDK4) downregulation and the KRAS mutation to deliver micellar nanoparticles (MNPs) containing small interfering RNA targeting CDK4 (MNPsiCDK4) for treatment in NSCLCs harboring the oncogenic KRAS mutation. Following MNPsiCDK4 administration, CDK4 expression was decreased, accompanied by inhibited cell proliferation, specifically in KRAS mutant NSCLCs. However, this intervention was harmless to normal KRAS wild-type cells, confirming the proposed mechanism of synthetic lethality. Moreover, systemic delivery of MNPsiCDK4 significantly inhibited tumor growth in an A549 NSCLC xenograft murine model, with depressed expression of CDK4 and mutational KRAS status, suggesting the therapeutic promise of MNPsiCDK4 delivery in KRAS mutant NSCLCs via a synthetic lethal interaction between KRAS and CDK4.

Cancer immunotherapies, which train the natural immune system to specifically kill tumor cells while sparing the healthy cells, have helped revolutionize cancer treatments and demonstrated promising clinical therapeutic benefits for decades. However, the therapeutic outcome of immunotherapies, even for the most successful immune checkpoint blockade (ICB) therapy, remains unsatisfactory in the clinical practice, mainly due to the low immunogenicity of solid tumors and its immunosuppressive tumor microenvironment (TME). Notably, several cancer treatment modalities, including chemotherapy, radiotherapy, and phototherapy, have been revealed to evoke tumor immunogenicity and reverse immunosuppressive TME via inducing immunogenic cell death (ICD) of tumor cells, which synergistically sensitized tumors to ICB therapy. Nanomedicines have been extensively applied to augment ICD-inducing treatment modalities and potentiate ICB therapeutic efficacy therapy due to the opportune convergence of immunotherapy and nanotechnology. Here, we discuss the recent advances in nanomedicine-mediated ICD and its combination with ICB therapy.

Nanoparticles as drug delivery systems are emerging as a class of therapeutics for cancer. pH‐activated nanoparticles have recently been developed for targeted drug delivery because of the acidic extracellular environment typical of solid tumors. Compared to conventional specific surface targeting of tumor cells, the pH targeting approach is considered to be more general because of the common occurrence of an acidic microenvironment in solid tumors. This chapter mainly focuses on the design and application of extracellular pH‐activated nanoparticles for drug and small interfering RNA (siRNA) delivery to tumors. The novel developments of nanoparticles described here offer great potential to achieve better therapeutic effects in cancer treatment.

Objectives To evaluate the feasibility of transcatheter closure ≥ ventricular septal defect (VSD). Methods 379 cases with ≥ 10 mmVSDs underwent attempted transcatheter closure with various devices in this study. Of those,166 were male and 213 were female. The age ranged from 3 to 70 (16.5 ± 14.3) years. Physical exam showed an accentuated pulmonic second heart sound and a grade 3 to 4 systolic murmur over the left third or fourth intercostal space. The left ventricular diameter of the defect on echocardiography ranged from 3 to 15 (4.6 ± 1.2) mm. Results VSDs was successfully closed in 376 of 379 patients (99.0% closure rate). The size of defect ranged from 10 to 32 (13.2 ± 3.3) mm at left ventricular side and from 3 to 16 (5.1 ± 2.5) mm at right ventricular side with distance from 0 to 11 (3.0) mm between aortic valve and the upper margin of the defect. Associated abnormalities were membraneous aneurysm in 318, PDA in7, ASD in 3 and PFO in 1 patients. The devices used to close VSDs and associated abnormalities were domestic-made devices including symmetrical VSD devices (n = 104), unsymmetrical VSD devices (n = 247), inequilateral VSD devices (n = 14), PDA devices (n = 7), ASD devices (n = 4), and foreign devices including Amplatzer unsymmetrical VSD devices (n = 10) and PDA devices (n = 1). The diameter of VSD devices ranged from 4 to 16 (7.55 ± 2.17) mm. The associated ASD and PDA were closed after VSD closure, while the muscular VSD were closed simultaneously with membraneous VSDs. Check cardiac angiography after device deployment showed complete closure in 350 (93.2%), trace residual shunt in 9 (2.5%) and small residual shunt in 17 (4.3%), but only 3 had residual shunt at discharge which were still at follow-up. Four patients developed third degree A-V block, which resolved itself in 3 but did not in one patient until the device was surgically taken out. Twelve patients developed transient complete left bundle branch block after the procedure, which resolved in 10 patients or developed incomplete left bundle branch block at follow up. Conclusions Large VSD is the relative indications for interventional therapy. Preoperative UCG must be strictly conducted to select the patients. The patients who had membranous aneurysm, the distance >2 mm from upper rim of VSD to the right aortic valve cusp or elder patients may have a higher success rate of interventional therapy. Standardised operational procedures, professional skills, multiple occlusion apparatus, short operation time, avoiding repetitive manipulations and reducing complications are the guarantee of success in interventional therapy of ≥10 mmVSDs.

Objectives To evaluate the value of transthoracic echocardiographic (TTE) in transcatheter closure of ventricular septal defects (VSD) in Children. Methods 855 patients aged 3∼14 years (average 6.8 years) with VSD were occluded, including 828 patients with membranous or perimembranous VSD, 9 patients with muscular VSD and 18 patients with intracristal VSD. TTE was performed before catheterization to examine the VSD and the rims, to evaluate the occluder device, and to evaluate the efficacy of the device occlusion on parasternal long axis of left ventricle, short axis of aorta and five chamber views. Results The size of VSD measured with TTE were 3.0∼7.0 mm (average 4.8 mm). Mild risidual shunt was revealed in 38 patients, which disappeared in 24∼48h after the procedure. At follow-up in 1m∼1y, TTE revealed 1 patient residual shunt. Conclusions TTE is a useful approach for the preliminary selectable of VSD in children, for decision of the procedure and enables determination of device size, correct placement of the device, assessment of the cosure procedure and result evaluation at follow-up.