ConspectusOver the past decades, major efforts were undertaken to develop devices on a nanoscale level for the efficient and nontoxic delivery of molecules to tissues and cells, for the purpose of either diagnosis or treatment of disease. The application of such devices in drug delivery has proven to be beneficial for matters as diverse as drug solubility, drug targeting, controlled drug release, and transport of drugs across cellular barriers. Multiple nanotherapeutics have been approved for clinical treatment, and more products are being evaluated in preclinical and clinical trials. However, many biological barriers hinder the medical application of nanocarriers. There are two main classes of barriers that need to be overcome by drug nanocarriers: extracellular and intracellular barriers, both of which may capture and/or destroy therapeutics before they reach their target site. This Account discusses major biological barriers that are confronted by nanotherapeutics, following their systemic administration, focusing on cellular entry and endosomal escape of gene delivery vectors. The use of pH-responsive materials to overcome the endosomal barrier is addressed.Historically, cell biologists have studied the interaction between cells and pathogens in order to unveil the mechanisms of endocytosis and cell signaling. Meanwhile, it is becoming clear that cells may respond in similar ways to artificial drug delivery systems and, consequently, that knowledge on the cellular response against both pathogens and nanoparticulate systems will aid in the design of improved nanomedicine. A close collaboration between bioengineers and cell biologists will promote this development. At the same time, we have come to realize that tools that we use to study fundamental cellular processes, including metabolic inhibitors of endocytosis and overexpression/downregulation of proteins, may cause changes in cellular physiology. This calls for the implementation of refined methods to study nanocarrier–cell interactions, as is discussed in this Account.Finally, recent papers on the dynamics of cargo release from endosomes by means of live cell imaging have significantly advanced our understanding of the transfection process. They have initiated discussion (among others) on the limited number of endosomal escape events in transfection, and on the endosomal stage at which genetic cargo is most efficiently released. Advancements in imaging techniques, including super-resolution microscopy, in concert with techniques to label endogenous proteins and/or label proteins with synthetic fluorophores, will contribute to a more detailed understanding of nanocarrier-cell dynamics, which is imperative for the development of safe and efficient nanomedicine.

It is extremely difficult for cancer chemotherapy to control the peritoneal metastasis of advanced ovarian carcinoma given its inability to target disseminated tumors and the severe toxic side effects on healthy organs. Here, we report antitumor M1 macrophages developed as live-cell carriers that deliver anticancer drugs for the treatment of the metastatic ovarian carcinoma. Engineered doxorubicin-loaded M1 macrophages (M1-Dox) significantly enhanced tumor tropism by upregulation of CCR2 and CCR4 compared with their parent cells. Meanwhile, M1-Dox inhibited doxorubicin-induced tumor invasion, whereas commercial Lipo-Dox did not limit these side effects. Importantly, our data uncovered a drug delivery mechanism by which M1-Dox transferred drug cargoes into tumor cells via a tunneling nanotube pathway. The tunneling nanotube network acted as a transportation expressway for ultrafast drug delivery of M1-Dox, leading to efficient ovarian carcinoma cell death. Furthermore, genetic, pharmacological, and physical perturbations of these tunneling nanotubes obviously decreased drug transfer of M1-Dox, which further validated the evident correlation between drug delivery of M1-Dox and tunneling nanotubes. Finally, in peritoneal metastatic ovarian carcinoma-burdened mice, M1-Dox specifically penetrated into and accumulated deep within disseminated neoplastic lesions compared with commercial Lipo-Dox, resulting in reducing metastatic tumors to a nearly undetectable level and significantly increasing overall survival. Overall, the strategy of engineered macrophages for ultrafast and accurate drug delivery via the tunneling nanotubular expressway potentially revolutionizes the treatment of metastatic ovarian carcinoma.

Advanced melanoma can rarely be cured. Photodynamic therapy (PDT) readily eradicates the primary melanoma but has limited ability to destroy the spreading tumor cells unless supported by other combinative interventions to augment systemic antitumor immunity. Based on the previously synthesized penetration‐enhancing biomaterials, a topically administered nanoformulation is developed, which profoundly assists 5‐aminolevulinic acid (5‐ALA) in circumventing skin barrier to be selectively delivered to tumor cells. After endocytosis, accumulated 5‐ALA is efficiently metabolized to a photosensitizer protoporphyrin IX (PpIX) which stimulates a large production of cytotoxic reactive oxygen species (ROS) under illumination. Accompanied by the robust inflammatory responses followed by primary tumor destruction, CD4+CD8+ double positive T cells are highly boosted to harness host immunity to purge metastases in lymphoid organs. Compared with dacarbazine and programmed death 1 (PD‐1) antibody, this treatment in advanced melanoma murine models, achieves a striking curable rate of 90% without melanoma prognostic markers LDH and S‐100B detection, followed by a relapse‐free survival rate of 83.33% in 300 days. Moreover, the cured mice's immune system function recovers to an extent similar to healthy mice without prolonged or exaggerated inflammation. This study using the synergistic biomaterials approach may thus render 5‐ALA‐mediated PDT a potentially curative therapy for advanced melanoma in clinic.

Sleep deprivation (SD) is very common in modern society and has a profound effect on cognitive function, in particular on working memory (WM). This type of memory is required for completion of many tasks and is adversely affected by SD. However, the cognitive neural mechanism by which SD affects WM, remains unclear. In this study, we investigated the changes in the brain network involved in WM after SD. Twentytwo healthy subjects underwent functional magnetic resonance imaging scan while in a state of resting wakefulness and again after 36 h of total SD and performed a WM task before each scanning session. Nineteen main nodes of the default mode network (DMN), dorsal attention network (DAN), fronto-parietal network (FPN), salience network (SN), and other networks were selected for functional analysis of brain network connections. Functional connectivity measures were computed between seed areas for region of interest (ROI)-to-ROI analysis and to identify patterns of ROI-to-ROI connectivity. The relationship between the significant changes in functional connectivity in the brain network and WM performance were then examined by Pearson's correlation analysis. WM performance declined significantly after SD. Compared with the awake state, the functional connectivity between DAN and DMN significantly increased after SD while that between FPN and DMN significantly decreased. Correlation analysis showed that the enhanced functional connectivity between DAN and DMN was negatively correlated with the decline in WM performance and that the decline in functional connectivity between FPN and DMN was positively correlated with decreased WM performance. These findings suggested that SD may affect WM by altering the functional connectivity among DMN, DAN, and FPN.

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Background: This study aimed to summarize the available data on the association between the severity of (COVID-19) and routine blood indicators, inflammatory, biochemical parameters and coagulation parameter.Methods: A literature search was conducted of PubMed, EMBASE, and Web of Sciences, CNKI, WanFang database providing relevant data. Random-effects meta-analysis was used to pool effect sizes.

It is not efficient enough using the current approaches for tumor-selective drug delivery based on the EPR effect and ligand-receptor interactions, and they have largely failed to translate into the clinic. Therefore, it is urgent to explore an enhanced strategy for effective delivery of anticancer agents. Clinically, many cancers require large amounts of glutamine for their continued growth and survival, resulting in circulating glutamine extraction by the tumor being much greater than that for any organs, behaving as a "glutamine trap". In the present study, we sought to elucidate whether the glutamine-trap effect could be exploited to deliver therapeutic agents to selectively kill cancer cells. Here, a macromolecular glutamine analogue, glutamine-functionalized branched polyethylenimine (GPI), was constructed as the carrier to deliver anti-CD47 siRNA for the blockage of CD47 "don't eat me" signals on cancer cells. The GPI/siRNA glutamine-rich polyplexes exhibited remarkably high levels of cellular uptake by glutamine-dependent lung cancer cells, wild-type A549 cells (A549), and its cisplatin-resistant cells (A549), specifically under glutamine-depleted conditions. It was noted that the glutamine transporter ASCT2 was highly expressed both on A549 and A549 but with almost no expression in normal human lung fibroblasts cells. Inhibition of ASCT2 significantly prevented the internalization of GPI polyplexes. These findings raised the intriguing possibility that the glutamine-rich GPI polyplexes utilize the ASCT2 pathway to selectively facilitate their cellular uptake by cancer cells. GPI further delivered anti-CD47 siRNA efficiently both in vitro and in vivo to downregulate the intratumoral mRNA and protein expression levels of CD47. CD47 functions as a "don't eat me" signal and binds to the immunoreceptor SIRPα inducing evasion of phagocytic clearance. GPI/anti-CD47 siRNA polyplexes achieved significant antitumor activities both on A549 and A549 tumor-bearing nude mice. Notably, it had no adverse effect on CD47-expressing red blood cells and platelets, likely because of selective delivery. Therefore, the glutamine-rich carrier GPI driven by the glutamine-trap effect provides a promising new strategy for designing anticancer drug delivery systems.