Global Prevalence and Hemagglutinin Evolution of H7N9 Avian Influenza Viruses from 2013 to 2022.

H7N9 avian influenza viruses have caused severe harm to the global aquaculture industry and human health. For further understanding of the characteristics of prevalence and hemagglutinin evolution of H7N9 avian influenza viruses, we generated the global epidemic map of H7N9 viruses from 2013 to 2022, constructed a phylogenetic tree, predicted the glycosylation sites and compared the selection pressure of the hemagglutinin. The results showed that although H7N9 avian influenza appeared sporadically in other regions worldwide, China had concentrated outbreaks from 2013 to 2017. The hemagglutinin genes were classified into six distinct lineages: A, B, C, D, E and F. After 2019, H7N9 viruses from the lineages B, E and F persisted, with the lineage B being the dominant. The hemagglutinin of highly pathogenic viruses in the B lineage has an additional predicted glycosylation site, which may account for their persistent pandemic, and is under more positive selection pressure. The most recent ancestor of the H7N9 avian influenza viruses originated in September 1991. The continuous evolution of hemagglutinin has led to an increase in virus pathogenicity in both poultry and humans, and sustained human-to-human transmission. This study provides a theoretical basis for better prediction and control of H7N9 avian influenza.

Modulating tumor mechanics with nanomedicine for cancer therapy.

Over the past several decades, the importance of the tumor mechanical microenvironment (TMME) in cancer progression or cancer therapy has been recognized by researchers worldwide. The abnormal mechanical properties of tumor tissues include high mechanical stiffness, high solid stress, and high interstitial fluid pressure (IFP), which form physical barriers resulting in suboptimal treatment efficacy and resistance to different types of therapy by preventing drugs infiltrating the tumor parenchyma. Therefore, preventing or reversing the establishment of the abnormal TMME is critical for cancer therapy. Nanomedicines can enhance drug delivery by exploiting the enhanced permeability and retention (EPR) effect, so nanomedicines that target and modulate the TMME can further boost antitumor efficacy. Herein, we mainly discuss the nanomedicines that can regulate mechanical stiffness, solid stress, and IFP, with a focus on how nanomedicines change abnormal mechanical properties and facilitate drug delivery. We first introduce the formation, characterizing methods and biological effects of tumor mechanical properties. Conventional TMME modulation strategies will be briefly summarized. Then, we highlight representative nanomedicines capable of modulating the TMME for augmented cancer therapy. Finally, current challenges and future opportunities for regulating the TMME with nanomedicines will be provided.

Mechano-boosting nanomedicine antitumour efficacy by blocking the reticuloendothelial system with stiff nanogels.

Nanomedicine has been developed for cancer therapy over several decades, while rapid clearance from blood circulation by reticuloendothelial system (RES) severely limits nanomedicine antitumour efficacy. We design a series of nanogels with distinctive stiffness and investigate how nanogel mechanical properties could be leveraged to overcome RES. Stiff nanogels are injected preferentially to abrogate uptake capacity of macrophages and temporarily block RES, relying on inhibition of clathrin and prolonged liver retention. Afterwards, soft nanogels deliver doxorubicin (DOX) with excellent efficiency, reflected in high tumour accumulation, deep tumour penetration and outstanding antitumour efficacy. In this work, we combine the advantage of stiff nanogels in RES-blockade with the superiority of soft nanogels in drug delivery leads to the optimum tumour inhibition effect, which is defined as mechano-boosting antitumour strategy. Clinical implications of stiffness-dependent RES-blockade are also confirmed by promoting antitumour efficacy of commercialized nanomedicines, such as Doxil and Abraxane.

Hydroxyethyl starch-folic acid conjugates stabilized theranostic nanoparticles for cancer therapy.

Small molecular prodrug-based nanomedicines with high drug-loading efficiency and tumor selectivity have attracted great attention for cancer therapy against solid tumors, including triple negative breast cancers (TNBC). However, abnormal tumor mechanical microenvironment (TMME) severely restricts antitumor efficacy of prodrug nanomedicines by limiting drug delivery and fostering cancer stem cells (CSCs). Herein, we employed carbamate disulfide bridged doxorubicin dimeric prodrug as pharmaceutical ingredient, marketed IR780 iodide as photothermal agent, and biocompatible hydroxyethyl starch-folic acid conjugates as amphiphilic surfactant to prepare a theranostic nanomedicine (FDINs), which could actively target at TNBC 4T1 tumor tissues and achieve reduction-responsive drug release with high glutathione concentration in cancer cells and CSCs. Importantly, in addition to directly causing damage to cancer cells and sensitizing chemotherapy, FDINs-mediated photothermal effect regulates aberrant TMME via reducing cancer associated fibroblasts and depleting extracellular matrix proteins, thereby normalizing intratumor vessel structure and function to facilitate drug and oxygen delivery. Furthermore, FDINs potently eliminate CSCs by disrupting unique CSCs niche and consuming intracellular GSH in CSCs. As a result, FDINs significantly suppress tumor growth in both subcutaneous and orthotopic 4T1 tumors. This study provides novel insights on rational design of prodrug nanomedicines for superior therapeutic effect against stroma- and CSCs-rich solid malignancies.

Precise fibrin decomposition and tumor mechanics modulation with hydroxyethyl starch-based smart nanomedicine for enhanced antitumor efficacy.

Chemotherapy is a conventional cancer treatment in clinical settings. Although numerous nano drug delivery systems have been developed, the chemotherapeutic effect is greatly limited by abnormal tumor mechanics in solid tumors. Tumor stiffening and accumulated solid stress compress blood vessels and inhibit drug delivery to tumor cells, becoming critical challenges for chemotherapy. By loading doxorubicin (DOX), tissue plasminogen activator (tPA), and fibrin targeting peptide CREKA (Cys-Arg-Glu-Lys-Ala) within pH responsive amphiphilic block polymers, pyridyldithio-hydroxyethyl starch-Schiff base-polylactic acid (PA-HES-pH-PLA), we report a smart nanomedicine, DOX@CREKA/tPA-HES-pH-PLA (DOX@CREKA/tPA-HP), which exhibits a potent antitumor efficacy. In triple-negative breast cancer (TNBC) 4T1 tumors, DOX@CREKA/tPA-HP precisely targeted and effectively decomposed fibrin matrix. By measuring Young's Modulus of tumor slices and quantifying tumor openings, we demonstrated that DOX@CREKA/tPA-HP remarkably reduced tumor stiffness and solid stress. Consequently, the alleviated tumor mechanics decompressed tumor blood vessels, promoted drug delivery, and led to amplified antitumor effect. Our work reveals that decomposing fibrin is a significant means for modulating tumor mechanics, and DOX@CREKA/tPA-HP is a promising smart nanomedicine for treating TNBC.

A DiR loaded tumor targeting theranostic cisplatin-icodextrin prodrug nanoparticle for imaging guided chemo-photothermal cancer therapy.

Imaging-guided diagnosis and chemo-photothermal combination therapy have promising applications for the treatment of cancer. Nevertheless, the accurate diagnosis and efficient treatment of tumors are not yet satisfactory. Herein, a tumor targeting DiR loaded cisplatin-icodextrin prodrug nanoparticle, with selective drug release, was fabricated as a multifunctional theranostic nanoplatform for chemo-photothermal combination therapy. By loading DiR into the hydrophobic domain of folic acid-icodextrin-polycaprolactone (FA-ICO-PCL, FIP) and cisplatin-icodextrin-polycaprolactone (Pt-ICO-PCL, PtIP) co-assembly, the resultant DiR@(PtIP + FIP) (DPtFIP) NPs had a diameter of around 70 nm and showed excellent tumor targeting ability and negligible side effects. Moreover, the DPtFIP NPs achieved real-time NIR fluorescence imaging of solid tumors with high contrast. By the accurate tumor imaging, local laser irradiation dramatically enhanced the chemotherapy for triple-negative breast cancer. Such a biocompatible nanotherapeutic holds great potential for tumor diagnosis and imaging-guided combinational cancer therapy.