Biomaterials

The limitations of traditional two-dimensional (2D) cultures and animal testing, when it comes to precisely foreseeing the toxicity and clinical effectiveness of potential drug candidates, have resulted in a notable increase in the rate of failure during the process of drug discovery and development. Three-dimensional (3D) in-vitro models have arisen as substitute platforms with the capacity to accurately depict in-vivo conditions and increasing the predictivity of clinical effects and toxicity of drug candidates...

Peptide amphiphile (PA) nanofibers have been shown to target and deliver drugs when administered via an intravenous (IV) injection. Subcutaneous administration can broaden the applicability of PA nanofibers in the medical field. The ability of PA nanofibers to be absorbed into systemic circulation after subcutaneous administration was investigated. Four PA molecules with different amino acid sequences were designed to understand the effect of nanofiber cohesion and charge on uptake. Solution small-angle X-ray scattering confirmed nanostructure morphology and provided characteristic lengths for co-assemblies...

Gene therapy has been adapted, from the laboratory to the clinic, to treat retinopathies. In contrast to subretinal route, intravitreal delivery of AAV vectors displays the advantage of bypassing surgical injuries, but the viral particles are more prone to be nullified by the host neutralizing factors. To minimize such suppression of therapeutic effect, especially in terms of AAV2 and its derivatives, we introduced three serine-to-glycine mutations, based on the phosphorylation sites identified by mass spectrum analysis, to the XL32 capsid to generate a novel serotype named AAVYC5...

During embryonic development, tissues must possess precise material properties to ensure that cell-generated forces give rise to the stereotyped morphologies of developing organs. However, the question of how material properties are established and regulated during development remains understudied. Here, we aim to address these broader questions through the study of intestinal looping, a process by which the initially straight intestinal tube buckles into loops, permitting ordered packing within the body cavity...

Idiopathic pulmonary fibrosis (IPF) stands as a highly heterogeneous and deadly lung disease, yet the available treatment options remain limited. Combining myofibroblast inhibition with ROS modulation in damaged AECs offers a comprehensive strategy to halt IPF progression, but delivering drugs separately to these cell types is challenging. Inspired by the successful application of pulmonary surfactant (PS) replacement therapy in lung disease treatment, we have developed PS nano-biomimetic liposomes (PSBs) to utilize its natural transport pathway for targeting AECs while reducing lung tissue clearance...

Nanodecoy systems based on analogues of viral cellular receptors assembled onto fluid lipid-based membranes of nano/extravescicles are potential new tools to complement classic therapeutic or preventive antiviral approaches. The need for lipid-based membranes for transmembrane receptor anchorage may pose technical challenges along industrial translation, calling for alternative geometries for receptor multimerization. Here we developed a semisynthetic self-assembling SARS-CoV-2 nanodecoy by multimerizing the biotin labelled virus cell receptor -ACE2- ectodomain onto a poly-avidin nanoparticle (NP) based on the Avidin-Nucleic-Acid-NanoASsembly-ANANAS...

Precise delivery of genes to therapy-relevant cells is crucial for in vivo gene therapy. Receptor-targeting as prime strategy for this purpose is limited to cell types defined by a single cell-surface marker. Many target cells are characterized by combinations of more than one marker, such as the HIV reservoir cells. Here, we explored the tropism of adeno-associated viral vectors (AAV2) displaying designed ankyrin repeat proteins (DARPins) mono- and bispecific for CD4 and CD32a. Cryo-electron tomography revealed an unaltered capsid structure in the presence of DARPins...

Reactive oxygen species (ROS) play a crucial role in regulating the metabolism of tumor growth, metastasis, death and other biological processes. ROS-based nanodynamic therapies (NDTs) are becoming attractive due to non-invasive, low side effects and tumor-specific advantages. NDTs have rapidly developed into numerous branches, such as photodynamic therapy, chemodynamic therapy, sonodynamic therapy and so on. However, the complexity of the tumor microenvironment and the limitations of existing sensitizers have greatly restricted the therapeutic effects of NDTs, which heavily rely on ROS levels...

Triple-negative breast cancer (TNBC) causes great suffering to patients because of its heterogeneity, poor prognosis, and chemotherapy resistance. Ferroptosis is characterized by iron-dependent oxidative damage by accumulating intracellular lipid peroxides to lethal levels, and plays a vital role in the treatment of TNBC based on its intrinsic characteristics. To identify the relationship between chemotherapy resistance and ferroptosis in TNBC, we analyzed the single cell RNA-sequencing public dataset of GSE205551...

Developing scalable vascularized and innervated tissue is a critical challenge for the successful clinical application of tissue-engineered constructs. Collagen hydrogels are extensively utilized in cell-mediated vascular network formation because of their naturally excellent biological properties. However, the substantial increase in hydrogel contraction induced by populated cells limits their long-term use. Previous studies attempted to mitigate this issue by concentrating collagen pre-polymer solutions or synthesizing covalently crosslinked collagen hydrogels...

Very large bone defects significantly diminish the vascular, blood, and nutrient supply to the injured site, reducing the bone's ability to self-regenerate and complicating treatment. Delivering nanomedicines from biomaterial scaffolds that induce host cells to produce bone-healing proteins is emerging as an appealing solution for treating these challenging defects. In this context, microRNA-26a mimics (miR-26a) are particularly interesting as they target the two most relevant processes in bone regeneration-angiogenesis and osteogenesis...

Critical limb ischemia (CLI) occurs when blood flow is restricted through the arteries, resulting in ulcers, necrosis, and chronic wounds in the downstream extremities. The development of collateral arterioles (i.e. arteriogenesis), either by remodeling of pre-existing vascular networks or de novo growth of new vessels, can prevent or reverse ischemic damage, but it remains challenging to stimulate collateral arteriole development in a therapeutic context. Here, we show that a gelatin-based hydrogel, devoid of growth factors or encapsulated cells, promotes arteriogenesis and attenuates tissue damage in a murine CLI model...

Tissue mechanobiology is an emerging field with the overarching goal of understanding the interplay between biophysical and biochemical responses affecting development, physiology, and disease. Changes in mechanical properties including stiffness and viscosity have been shown to describe how cells and tissues respond to mechanical cues and modify critical biological functions. To quantitatively characterize the mechanical properties of tissues at physiologically relevant conditions, atomic force microscopy (AFM) has emerged as a highly versatile biomechanical technology...

Rheumatoid arthritis (RA) is one of the most prevalent life-long autoimmune diseases with an unknown genesis. It primarily causes chronic inflammation, pain, and synovial joint-associated cartilage and bone degradation. Unfortunately, limited information is available regarding the etiology and pathogenesis of this chronic joint disorder. In the last few decades, an improved understanding of RA pathophysiology about key immune cells, antibodies, and cytokines has inspired the development of several anti-rheumatic drugs and biopharmaceuticals to act on RA-affected joints...

Tumor cells overexpress programmed cell death ligand 1 (PD-L1) to impede immune responses and escape immune elimination. Development of effective combination regimens to sensitize immunotherapy is promising but always challenging. Herein, a self-reinforced photodynamic immunostimulator (designated as PCS) is constructed for metastatic breast cancer treatment through simultaneous downregulation and blockade of PD-L1. Specifically, PCS is prepared by encapsulating signal transducer and activator of transcription 3 (STAT3) inhibitor (Stattic) into photosensitizer (protoporphyrin IX) modified PD-L1 blockade peptide (CVRARTR) through drug self-assembly...

Drug synergy has made significant strides in clinical applications in recent decades. However, achieving a platform that enables "single administration, multi-stage release" by emulating the natural physiological processes of the human body poses a formidable challenge in the field of molecular pharmaceutics. Hydrogels, as the novel generation of drug delivery systems, have gained widespread utilization in drug platforms owing to their exceptional biocompatibility and modifiability. Sequential drug delivery hydrogels (SDDHs), which amalgamate the advantages of hydrogel and sequential release platforms, offer a promising solution for effectively navigating the intricate human environment and accomplishing drug sequential release...

Spinal cord injuries have devastating consequences for humans, as mammalian neurons of the central nervous system (CNS) cannot regenerate. In the peripheral nervous system (PNS), however, neurons may regenerate to restore lost function following injury. While mammalian CNS tissue softens after injury, how PNS tissue mechanics changes in response to mechanical trauma is currently poorly understood. Here we characterised mechanical rat nerve tissue properties before and after in vivo crush and transection injuries using atomic force microscopy-based indentation measurements...

Systemic injection of thrombolytic drugs is the gold standard treatment for non-invasive blood clot resolution. The most serious risks associated with the intravenous injection of tissue plasminogen activator-like proteins are the bleeding complication and the dose related neurotoxicity. Indeed, the drug has to be injected in high concentrations due to its short half-life, the presence of its natural blood inhibitor (PAI-1) and the fast hepatic clearance (0.9 mg/kg in humans, 10 mg/kg in mouse models)...

Endochondral ossification (ECO), the major ossification process during embryogenesis and bone repair, involves the formation of a cartilaginous template remodelled into a functional bone organ. Adipose-derived stromal cells (ASC), non-skeletal multipotent progenitors from the stromal vascular fraction (SVF) of human adipose tissue, were shown to recapitulate ECO and generate bone organs in vivo when primed into a hypertrophic cartilage tissue (HCT) in vitro. However, the reproducibility of ECO was limited and the major triggers remain unknown...

Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment which promotes the formation of the immunosuppressive tumor microenvironment (ITME) through multiple mechanisms, severely counteracting the therapeutic efficacy of immunotherapy. In this study, a novel biomimetic ferroptosis inducer (D@FMN-M) capable of ITME regulation for enhanced cancer ferroptosis immunotherapy is reported. Upon tumor accumulation of D@FMN-M, the intratumoral mild acidity triggers the biodegradation of Fe-enriched nanocarriers and the concurrent co-releases of dihydroartemisinin (DHA) and Fe3+ ...