Ultrasound-Based Micro-/Nanosystems for Biomedical Applications.

Due to the intrinsic non-invasive nature, cost-effectiveness, high safety, and real-time capabilities, besides diagnostic imaging, ultrasound as a typical mechanical wave has been extensively developed as a physical tool for versatile biomedical applications. Especially, the prosperity of nanotechnology and nanomedicine invigorates the landscape of ultrasound-based medicine. The unprecedented surge in research enthusiasm and dedicated efforts have led to a mass of multifunctional micro-/nanosystems being applied in ultrasound biomedicine, facilitating precise diagnosis, effective treatment, and personalized theranostics. The effective deployment of versatile ultrasound-based micro-/nanosystems in biomedical applications is rooted in a profound understanding of the relationship among composition, structure, property, bioactivity, application, and performance. In this comprehensive review, we elaborate on the general principles regarding the design, synthesis, functionalization, and optimization of ultrasound-based micro-/nanosystems for abundant biomedical applications. In particular, recent advancements in ultrasound-based micro-/nanosystems for diagnostic imaging are meticulously summarized. Furthermore, we systematically elucidate state-of-the-art studies concerning recent progress in ultrasound-based micro-/nanosystems for therapeutic applications targeting various pathological abnormalities including cancer, bacterial infection, brain diseases, cardiovascular diseases, and metabolic diseases. Finally, we conclude and provide an outlook on this research field with an in-depth discussion of the challenges faced and future developments for further extensive clinical translation and application.

Adjuvant physiochemistry and advanced nanotechnology for vaccine development.

Vaccines comprising innovative adjuvants are rapidly reaching advanced translational stages, such as the authorized nanotechnology adjuvants in mRNA vaccines against COVID-19 worldwide, offering new strategies to effectively combat diseases threatening human health. Adjuvants are vital ingredients in vaccines, which can augment the degree, extensiveness, and longevity of antigen specific immune response. The advances in the modulation of physicochemical properties of nanoplatforms elevate the capability of adjuvants in initiating the innate immune system and adaptive immunity, offering immense potential for developing vaccines against hard-to-target infectious diseases and cancer. In this review, we provide an essential introduction of the basic principles of prophylactic and therapeutic vaccination, key roles of adjuvants in augmenting and shaping immunity to achieve desired outcomes and effectiveness, and the physiochemical properties and action mechanisms of clinically approved adjuvants for humans. We particularly focus on the preclinical and clinical progress of highly immunogenic emerging nanotechnology adjuvants formulated in vaccines for cancer treatment or infectious disease prevention. We deliberate on how the immune system can sense and respond to the physicochemical cues (e.g., chirality, deformability, solubility, topology, and chemical structures) of nanotechnology adjuvants incorporated in the vaccines. Finally, we propose possible strategies to accelerate the clinical implementation of nanotechnology adjuvanted vaccines, such as in-depth elucidation of nano-immuno interactions, antigen identification and optimization by the deployment of high-dimensional multiomics analysis approaches, encouraging close collaborations among scientists from different scientific disciplines and aggressive exploration of novel nanotechnologies.

Constitutive Gαi coupling activity of very large G protein-coupled receptor 1 (VLGR1) and its regulation by PDZD7 protein.

The very large G protein-coupled receptor 1 (VLGR1) is a core component in inner ear hair cell development. Mutations in the vlgr1 gene cause Usher syndrome, the symptoms of which include congenital hearing loss and progressive retinitis pigmentosa. However, the mechanism of VLGR1-regulated intracellular signaling and its role in Usher syndrome remain elusive. Here, we show that VLGR1 is processed into two fragments after autocleavage at the G protein-coupled receptor proteolytic site. The cleaved VLGR1 ß-subunit constitutively inhibited adenylate cyclase (AC) activity through Gαi coupling. Co-expression of the Gαiq chimera with the VLGR1 ß-subunit changed its activity to the phospholipase C/nuclear factor of activated T cells signaling pathway, which demonstrates the Gαi protein coupling specificity of this subunit. An R6002A mutation in intracellular loop 2 of VLGR1 abolished Gαi coupling, but the pathogenic VLGR1 Y6236fsx1 mutant showed increased AC inhibition. Furthermore, overexpression of another Usher syndrome protein, PDZD7, decreased the AC inhibition of the VLGR1 ß-subunit but showed no effect on the VLGR1 Y6236fsx1 mutant. Taken together, we identified an independent Gαi signaling pathway of the VLGR1 ß-subunit and its regulatory mechanisms that may have a role in the development of Usher syndrome.

Immunogenic Material Vaccine for Cancer Immunotherapy by Structure-Dependent Immune Cell Trafficking and Modulation.

Inherently immunogenic materials offer enormous prospects in enhancing vaccine efficacy. However, the understanding and improving material adjuvanticity remain elusive. Herein how the structural presentation of immunopotentiators in a material governs the dynamic dialogue between innate and adaptive immunity for enhanced cancer vaccination is reported. The immunopotentiator manganese into six differing structures that resemble the architectures of two types of pathogens (spherical viruses or rod-like bacteria) is precisely manipulated. The results reveal that innate immune cells accurately sense and respond to the architectures, of which two outperformed material candidates (151 nm hollow spheres and hollow microrods with an aspect ratio of 4.5) show higher competence in creating local proinflammatory environment with promoted innate immune cell influx and stimulation on dendritic cells (DCs). In combination with viral peptides, model proteins, or cell lysate antigens, the outperformed microrod material remarkably primes antigen-specific CD8 cytolytic T cells. In prophylactic and therapeutic regimens, the microrod adjuvanted vaccines display optimal aptitude in tumor suppression in four aggressive murine tumor models, by promoting the infiltration of heterogeneous cytolytic effector cells while decreasing suppressive immunoregulatory populations in tumors. This study demonstrates that a rationally selected architecture of immunogenic materials potentially advances the clinical reality of cancer vaccination.

The very large G protein coupled receptor (Vlgr1) in hair cells.

The very large G protein coupled receptor (Vlgr1) is a member of adhesion receptors or large N-terminal family B-7 transmembrane helixes (LNB7TM) receptors within the seven trans-membrane receptor superfamily. Vlgr1 is the largest GPCR identified to date; its mRNA spans 19 kb and encodes 6,300 amino acids. Vlgr1 is a core component of ankle-link complex in inner ear hair cells. Knock-out and mutation mouse models show that loss of Vlgr1 function leads to abnormal stereociliary development and hearing loss, indicating crucial roles of Vlgr1 in hearing transduction or auditory system development. Over the past 10 or so years, human genetics data suggested that Vlgr1 mutations cause Usher syndromes and seizures. Although significant progresses have been made, the details of Vlgr1's function in hair cells, its signaling cascade, and the mechanisms underlying causative effects of Vlgr1 mutations in human diseases remain elusive and ask for further investigation.