In situ forming an injectable hyaluronic acid hydrogel for drug delivery and synergistic tumor therapy.

Stimulus-responsive injectable hydrogel has the key characteristics of in situ drug-loading ability and the controlled drug release, enabling efficient delivery and precise release of chemotherapy drugs at the tumor site, thereby being used as a local drug delivery system for sustained tumor treatment. This article designed a smart responsive injectable hydrogel loaded with anti-tumor drugs and nanoparticles to achieve efficient and specific synergistic treatment of tumors. Hyaluronic acid (HA) hydrogel obtained by cross-linking HA-SH (HS) and HA-Tyr (HT) through horseradish peroxidase (HRP), and doxorubicin hydrochloride (DOX) and folic acid-polyethylene glycol-amine (FA-PEG-NH2) modified PDA (denoted as PPF) were encapsulated to construct the HS/HT@PPF/D hydrogel. The hydrogel had good biocompatibility, injectability, and could respond to multiple stimuli at the tumor site, thereby achieving controlled drug release. At the same time, PPF gave it excellent photothermal efficiency, photothermal stability and tumor targeting. In vitro and in vivo experimental results showed that the HS/HT@PPF/D hydrogel combined with near-infrared laser irradiation could significantly improve its anti-tumor effect and could almost eliminate the entire tumor mass without obvious adverse reactions. The HS/HT@PPF/D hydrogel could achieve multi-stimulus-responsive drug delivery and be used for precise chemo-photothermal synergistic tumor treatment, thus providing a new platform for local synergistic tumor treatment.

Engineering Core/Ligands Interfacial Anchors of Nanoparticles for Efficiently Inhibiting Both Aß and Amylin Fibrillization.

Accurate construction of artificial nano-chaperones' structure is crucial for precise regulation of protein conformational transformation, facilitating effective treatment of proteopathy. However, how the ligand-anchors of nano-chaperones affect the spatial conformational changes in proteins remains unclear, limiting the development of efficient nano-chaperones. In this study, three types of gold nanoparticles (AuNPs) with different core/ligands interface anchor structures (Au─NH─R, Au─S─R, and Au─C≡C─R, R = benzoic acid) are synthesized as an ideal model to investigate the effect of interfacial anchors on Aß and amylin fibrillization. Computational results revealed that the distinct interfacial anchors imparted diverse distributions of electrostatic potential on the nanointerface and core/ligands bond strength of AuNPs, leading to differential interactions with amyloid peptides. Experimental results demonstrated that all three types of AuNPs exhibit site-specific inhibitory effects on Aß40 fibrillization due to preferential binding. For amylin, amino-anchored AuNPs demonstrate strong adsorption to multiple sites on amylin and effectively inhibit fibrillization. Conversely, thiol- and alkyne-anchored AuNPs adsorb at the head region of amylin, promoting folding and fibrillization. This study not only provided molecular insights into how core/ligands interfacial anchors of nanomaterials induce spatial conformational changes in amyloid peptides but also offered guidance for precisely engineering artificial-chaperones' nanointerfaces to regulate the conformational transformation of proteins.

Charge Effect of Mercaptobenzimidazole-Modified Ultrasmall Gold-Nanoparticles against Drug-Resistant Bacteria.

The threat of bacterial infections, especially drug-resistant strains, to human health necessitates the development of high-efficient, broad-spectrum and nonantibiotic nanodisinfectant. However, the effect of interfacial charge on the antibacterial properties of nanodisinfectant remains a mystery, which greatly limits the development of highly antibacterial active nanodisinfectant. Herein, we developed three types of ultrasmall (d < 3 nm) gold-nanoparticles (AuNPs) modified with 5-carboxylic(C)/methoxy(M)amino(A)/-2-mercaptobenzimidazole (C/M/A MB) to investigate their interfacial charge on antibacterial performance. Our results showed that both the electropositive AMB-AuNPs and electronegative CMB-AuNPs exhibited no antibacterial activity against both Gram-positive (G+) and Gram-negative (G-) bacteria. However, the electroneutral MMB-AuNPs exhibited unique antibacterial performance against both G+ and G- bacteria, even against methicillin-resistant Staphylococcus aureus (MRSA). Mechanistic investigation revealed a multipathway synergistic bacteriostatic mechanism involving MMB-AuNPs inducing damage to bacterial cell membranes, disruption of membrane potential and downregulation of ATP levels, ultimately leading to bacterial demise. Furthermore, two additional electroneutral AuNPs modified with 5-methyl-2-mercaptobenzimidazole (mMB-AuNPs) and 5-ethoxy-2-mercaptobenzimidazole (EMB-AuNPs) also demonstrated commendable antibacterial efficacy against E. coli, S. aureus, and MRSA; however, their performance was comparatively inferior to that of MMB-AuNPs. This work provides valuable insights for the development of high-performance antibacterial nanomaterials.

Improving Three-Photon Fluorescence of Near-Infrared Quantum Dots for Deep Brain Imaging by Suppressing Biexciton Decay.

Three-photon fluorescence microscopy (3PFM) is a promising brain research tool with submicrometer spatial resolution and high imaging depth. However, only limited materials have been developed for 3PFM owing to the rigorous requirement of the three-photon fluorescence (3PF) process. Herein, under the guidance of a band gap engineering strategy, CdTe/CdSe/ZnS quantum dots (QDs) emitting in the near-infrared window are designed for constructing 3PF probes. The formation of type II structure significantly increased the three-photon absorption cross section of QDs and caused the delocalization of electron-hole wave functions. The time-resolved transient absorption spectroscopy confirmed that the decay of biexcitons was significantly suppressed due to the appropriate band gap alignment, which further enhanced the 3PF efficiency of QDs. By utilizing QD-based 3PF probes, high-resolution 3PFM imaging of cerebral vasculature was realized excited by a 1600 nm femtosecond laser, indicating the possibility of deep brain imaging with these 3PF probes.

Palladium-Catalyzed Domino Heck/Cross-Coupling Cyclization Reaction: Diastereoselective Synthesis of Furan-Containing Indolines.

Herein, a palladium-catalyzed diastereoselective dearomatization/cross-coupling cyclization reaction between N-arylacyl indoles and (E)-ß-chlorovinyl ketones is reported. Through this cyclization/cycloisomerization cascade, a series of furan-containing indolines were obtained in yields up to 95%. The reaction features readily accessible starting materials, benzyl Pd(II)-catalyzed cycloisomerization of (E)-ß-chlorovinyl ketones, the sequential formation of three bonds and bis-heterocycles, and excellent diastereoselectivity. More importantly, the carbene-secondary benzyl migratory insertion is proven to be a critical process in the sequential cyclizations.

In vivo assembly enhanced binding effect augments tumor specific ferroptosis therapy.

Emerging evidence indicates that the activation of ferroptosis by glutathione peroxidase 4 (GPX4) inhibitors may be a prominent therapeutic strategy for tumor suppression. However, the wide application of GPX4 inhibitors in tumor therapy is hampered due to poor tumor delivery efficacy and the nonspecific activation of ferroptosis. Taking advantage of in vivo self-assembly, we develop a peptide-ferriporphyrin conjugate with tumor microenvironment specific activation to improve tumor penetration, endocytosis and GPX4 inhibition, ultimately enhancing its anticancer activity via ferroptosis. Briefly, a GPX4 inhibitory peptide is conjugated with an assembled peptide linker decorated with a pH-sensitive moiety and ferriporphyrin to produce the peptide-ferriporphyrin conjugate (Gi-F-CAA). Under the acidic microenvironment of the tumor, the Gi-F-CAA self-assembles into large nanoparticles (Gi-F) due to enhanced hydrophobic interaction after hydrolysis of CAA, improving tumor endocytosis efficiency. Importantly, Gi-F exhibits substantial inhibition of GPX4 activity by assembly enhanced binding (AEB) effect, augmenting the oxidative stress of ferriporphyrin-based Fenton reaction, ultimately enabling antitumor properties in multiple tumor models. Our findings suggest that this peptide-ferriporphyrin conjugate design with AEB effect can improve the therapeutic effect via induction of ferroptosis, providing an alternative strategy for overcoming chemoresistance.

Spatiotemporally controlled AuNPs@ZIF-8 based nanocarriers for synergistic photothermal/chemodynamic therapy.

High efficiency and spatio-temporal control remains a challenge for multi-modal synergistic cancer therapy. Herein, based on gold nanoparticles (AuNPs) and zeolite-like imidazole skeleton material (ZIF-8), a spatio-temporal controllable photothermal/ chemical dynamic/ chemotherapy three modal synergistic anti-tumor nano-carrier (HAZD) was developed. HAZD has a size of 128.75 ± 11.86 nm, a drug loading ratio of 21.5 ± 2.2 % and an encapsulation efficiency of 71.8 ± 1.7 %. Stability, acid responsive release character, outstanding catalytic ability to generate ROS, relatively high thermal conversion efficiency up to 62.38 % and spatio-temporal controllable abilities are also found within this nano-carrier. Furthermore, HAZD performed good antitumor ability in vivo with the comprehensive effects of photothermal/ chemical dynamic/ chemotherapy. The tumor growth inhibition value is 97.1 % within 12 days, indicating its great potential in multi-modal synergistic cancer therapy. STATEMENT OF SIGNIFICANCE: Cancer remains one of the major culprits that seriously harm human health currently. With the development of materials and nanotechnology, great improvements have been made in multimodal anti-tumor strategies. However, temporal- and spatial-controllable multi-modal synergistic nanocarriers are urgently awaited for efficient and low-toxicity tumor therapy. This article proposes a spatio-temporally controllable three-modal anti-tumor strategy and designs an anti-tumor drug delivery system based on gold nanoparticles (AuNPs) and zeolite-like imidazole skeleton material (ZIF-8), which shows acid-responsive release characteristics, catalytic ability to generate ROS, relatively high thermal conversion efficiency up to 62.38 %, as well as spatio-temporal controllable abilities. Moreover, it demonstrates outstanding anti-tumor ability, with a tumor growth inhibition value of 97.1 % within 12 days, revealing its significant potential for future personalized and precise anti-tumor treatments.

HFD-exacerbated Metabolic Side Effects of Olanzapine Are Suppressed by ER Stress Inhibitor.

OBJECTIVE: Numerous schizophrenic patients are suffering from obesity primarily attributed to antipsychotic medication and poor dietary habits. This study investigated the progressive deterioration of olanzapine-induced metabolic disorders in the presence of a high-fat diet (HFD) and explored the involvement of endoplasmic reticulum (ER) stress. METHODS: Female Sprague-Dawley rats fed on a standard chow diet or HFD were treated with olanzapine (3 mg/kg/day) and the ER stress inhibitor 4-phenylbutyric acid (4-PBA, 1 and 0.5 g/kg/day) for 8 days. Changes in body weight, food intake, and plasma lipids were assessed. Hepatic fat accumulation was evaluated using oil red O staining. Western blotting and immunofluorescence assays were employed to examine the expression of ER stress markers, NOD-like receptor pyrin domain-containing protein 3 (NLRP3), and proopiomelanocortin (POMC) in the hypothalamus or liver. RESULTS: Compared to olanzapine alone, olanzapine+HFD induced greater weight gain, increased hyperlipidemia, and enhanced hepatic fat accumulation (P<0.05). Co-treatment with 4-PBA exhibited a dose-dependent inhibition of these effects (P<0.05). Further mechanistic investigations revealed that olanzapine alone activated ER stress, upregulated NLRP3 expression in the hypothalamus and liver, and downregulated hypothalamic POMC expression. The HFD exacerbated these effects by 50%-100%. Moreover, co-administration of 4-PBA dose-dependently attenuated the olanzapine+HFD-induced alterations in ER stress, NLRP3, and POMC expression in the hypothalamus and liver (P<0.05). CONCLUSION: HFD worsened olanzapine-induced weight gain and lipid metabolic disorders, possibly through ER stress-POMC and ER stress-NLRP3 signaling. ER stress inhibitors could be effective in preventing olanzapine+HFD-induced metabolic disorders.

White matter changes in Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease (AD). It is characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and the formation of Lewy bodies (LBs). Although PD is primarily considered a gray matter (GM) disease, alterations in white matter (WM) have gained increasing attention in PD research recently. Here we review evidence collected by magnetic resonance imaging (MRI) techniques which indicate WM abnormalities in PD, and discuss the correlations between WM changes and specific PD symptoms. Then we summarize transcriptome and genome studies showing the changes of oligodendrocyte (OLs)/myelin in PD. We conclude that WM abnormalities caused by the changes of myelin/OLs might be important for PD pathology, which could be potential targets for PD treatment.

Molecularly Engineered Room-Temperature Phosphorescence for Biomedical Application: From the Visible toward Second Near-Infrared Window.

Phosphorescence, characterized by luminescent lifetimes significantly longer than that of biological autofluorescence under ambient environment, is of great value for biomedical applications. Academic evidence of fluorescence imaging indicates that virtually all imaging metrics (sensitivity, resolution, and penetration depths) are improved when progressing into longer wavelength regions, especially the recently reported second near-infrared (NIR-II, 1000-1700 nm) window. Although the emission wavelength of probes does matter, it is not clear whether the guideline of "the longer the wavelength, the better the imaging effect" is still suitable for developing phosphorescent probes. For tissue-specific bioimaging, long-lived probes, even if they emit visible phosphorescence, enable accurate visualization of large deep tissues. For studies dealing with bioimaging of tiny biological architectures or dynamic physiopathological activities, the prerequisite is rigorous planning of long-wavelength phosphorescence, being aware of the cooperative contribution of long wavelengths and long lifetimes for improving the spatiotemporal resolution, penetration depth, and sensitivity of bioimaging. In this Review, emerging molecular engineering methods of room-temperature phosphorescence are discussed through the lens of photophysical mechanisms. We highlight the roles of phosphorescence with emission from visible to NIR-II windows toward bioapplications. To appreciate such advances, challenges and prospects in rapidly growing studies of room-temperature phosphorescence are described.

Development and challenges of antimicrobial peptide delivery strategies in bacterial therapy: A review.

The escalating global prevalence of antimicrobial resistance poses a critical threat, prompting concerns about its impact on public health. This predicament is exacerbated by the acute shortage of novel antimicrobial agents, a scarcity attributed to the rapid surge in bacterial resistance. This review delves into the realm of antimicrobial peptides, a diverse class of compounds ubiquitously present in plants and animals across various natural organisms. Renowned for their intrinsic antibacterial activity, these peptides provide a promising avenue to tackle the intricate challenge of bacterial resistance. However, the clinical utility of peptide-based drugs is hindered by limited bioavailability and susceptibility to rapid degradation, constraining efforts to enhance the efficacy of bacterial infection treatments. The emergence of nanocarriers marks a transformative approach poised to revolutionize peptide delivery strategies. This review elucidates a promising framework involving nanocarriers within the realm of antimicrobial peptides. This paradigm enables meticulous and controlled peptide release at infection sites by detecting dynamic shifts in microenvironmental factors, including pH, ROS, GSH, and reactive enzymes. Furthermore, a glimpse into the future reveals the potential of targeted delivery mechanisms, harnessing inflammatory responses and intricate signaling pathways, including adenosine triphosphate, macrophage receptors, and pathogenic nucleic acid entities. This approach holds promise in fortifying immunity, thereby amplifying the potency of peptide-based treatments. In summary, this review spotlights peptide nanosystems as prospective solutions for combating bacterial infections. By bridging antimicrobial peptides with advanced nanomedicine, a new therapeutic era emerges, poised to confront the formidable challenge of antimicrobial resistance head-on.

MicroRNA therapeutics and nucleic acid nano-delivery systems in bacterial infection: a review.

Bacteria that have worked with humans for thousands of years pose a major threat to human health even today, as drug resistance has become a prominent problem. Compared to conventional drug therapy, nucleic acid-based therapies are a promising and potential therapeutic strategy for diseases in which nucleic acids are delivered through a nucleic acid delivery system to regulate gene expression in specific cells, offering the possibility of curing intractable diseases that are difficult to treat at this stage. Among the many nucleic acid therapeutic ideas, microRNA, a class of small nucleic acids with special properties, has made great strides in biology and medicine in just over two decades, showing promise in preclinical drug development. In this review, we introduce recent advances in nucleic acid delivery systems and their clinical applications, highlighting the potential of nucleic acid therapies, especially miRNAs extracted from traditional herbs, in combination with the existing set of nucleic acid therapeutic systems, to potentially open up a new line of thought in the treatment of cancer, viruses, and especially bacterial infectious diseases.

Band Gap Engineering Improves Three-Photon Luminescence of Quantum Dots for Deep Brain Imaging.

Three-photon fluorescence microscopy (3PFM) has emerged as a promising tool in monitoring the structures and functions of the brain. Compared to the various imaging technologies, 3PFM enables a deep-penetrating depth attributed to tighter excitation confinement and suppressed photon scattering. However, the shortage of three-photon probes with a large absorption cross section (σ3) substantially limits its uses. Herein, CdSe/CdS/ZnS quantum dots (QDs) with enhanced 3PF performance were synthesized via the band gap engineering strategy. The introduction of a CdS interlayer with optimized thickness between the emitting CdSe core and the ZnS shell significantly enhanced the 3P absorption cross section of QDs, which originated from the intrinsic piezoelectric polarization effect and the change of the core/shell structure from type-I to quasi-type-II. In addition, the outer ZnS layer compensated the poor electronic passivation of CdS, providing a high level of passivation for the improvement of quantum yield as well as the 3P action cross section of QDs. Under the excitation of a 1600 nm femtosecond laser, PEGylated CdSe/CdS/ZnS QDs were used for in vivo 3PFM imaging of cerebral vessels with high resolution. A tiny capillary with a diameter of 0.8 µm could be resolved at the imaging depth of 1550 µm in a mouse brain with an opened skull. A penetration depth of 850 µm beneath the skull was also achieved using a mouse model with an intact skull.

Research progress of nanoparticle targeting delivery systems in bacterial infections.

Bacterial infection is a huge threat to the health of human beings and animals. The abuse of antibiotics have led to the occurrence of bacterial multidrug resistance, which have become a difficult problem in the treatment of clinical infections. Given the outstanding advantages of nanodrug delivery systems in cancer treatment, many scholars have begun to pay attention to their application in bacterial infections. However, due to the similarity of the microenvironment between bacterial infection lesions and cancer sites, the targeting and accuracy of traditional microenvironment-responsive nanocarriers are questionable. Therefore, finding new specific targets has become a new development direction of nanocarriers in bacterial prevention and treatment. This article reviews the infectious microenvironment induced by bacteria and a series of virulence factors of common pathogenic bacteria and their physiological functions, which may be used as potential targets to improve the targeting accuracy of nanocarriers in lesions.

Flexibility Analysis of DNA Nanotubes with Prescribed Circumferences and Their Pearl-Necklace Assemblies with Gold Nanoclusters.

DNA has been demonstrated as a powerful platform for the construction of inorganic nanoparticles (NPs) into complex three-dimensional assemblies. Despite extensive research, the physical fundamental details of DNA nanostructures and their assemblies with NPs remain obscure. Here, we report the identification and quantification of the assembly details of programmable DNA nanotubes with monodisperse circumferences of a 4, 5, 6, 7, 8, or 10 DNA helix and their pearl-necklace-like assemblies with ultrasmall gold nanoparticles, Au25 nanoclusters (AuNCs), liganded by -S(CH2)nNH3+ (n = 3, 6, 11). The flexibilities of DNA nanotubes, analyzed via statistical polymer physics analysis through atomic force microscopy (AFM), demonstrate that ∼2.8 power exponentially increased with the DNA helix number. Moreover, the short-length liganded AuS(CH2)3NH3+ NCs were observed to be able to form pearl-necklace-like DNA-AuNC assemblies stiffened than neat DNA nanotubes, while long-length liganded AuS(CH2)6NH3+ and AuS(CH2)11NH3+ NCs could fragment DNA nanotubular structures, indicating that DNA-AuNC assembling can be precisely manipulated by customizing the hydrophobic domains of the AuNC nanointerfaces. We prove the advantages of polymer science concepts in unraveling useful intrinsic information on physical fundamental details of DNA-AuNC assembling, which facilitates DNA-metal nanocomposite construction.

Physicochemical properties, pharmacokinetics, toxicology and application of nanocarriers.

As a promising delivery nanosystem for drug controlled-release, nanocarriers (NCs) have been investigated widely. Although various studies have concentrated on the preparation and characterization of nanoparticles (NPs), clinical applications are rarely reported, due to the unclear distribution, absorption, metabolism, toxicology processes and drug release mechanism. The clinical application of NCs is therefore still a long way off. This review describes the effects of the properties of NCs (including size, shape, surface properties, porosity, elasticity and so on) on pharmacological and toxicological behaviours in vivo and medical applications. Moreover, this study is intended to help the readers understand the behaviours and mechanisms of NCs and positively face the challenges caused by the variety of complicated and limited processes of NCs in vivo. Importantly, this article provides some strategies for the clinical application of NCs and may provide ideas to enhance the therapeutic efficacy of NCs without increasing the toxicology, by introducing tracing technology, which can be more suitable in contributing to the development of safety and efficacy of NCs and the growth of nanotechnology.

Gold Nanoclusters Enhance the Efficacy of the Polymer-Based Chaperone in Restoring and Maintaining the Native Conformation of Human Islet Amyloid Polypeptide.

The misfolding and un-natural fibrillation of proteins/peptides are associated with many conformation diseases, such as human islet amyloid polypeptide (hIAPP) in type 2 diabetes (T2D). Inspired by molecular chaperones maintaining protein homeostasis in vivo, many polymer-based artificial chaperones were introduced to regulate protein/peptide folding and fibrillation. However, the pure polymer chaperones prefer to agglomerate into large-size micelles in the physiological environment and thus lose their chaperone functions, which greatly restricts the application of polymer-based chaperones. Here, we designed and prepared a core-shell artificial chaperone based on a dozen poly-(N-isopropylacrylamide-co-N-acryloyl-O-methylated-l-arginine) (PNAMR) anchored on a gold-nanocluster (AuNC) core. The introduction of the AuNC core significantly reduced the size and enhanced the efficacy and stability of polymer-based artificial chaperones. The PNAMR@AuNCs, with a diameter of 2.5 ± 0.5 nm, demonstrated exceptional ability in maintaining the natively unfolded conformation of protein away from the misfolding and the following fibrillation by directly binding to the natively unfolded monomolecular hIAPP and hence in preventing their conversion into toxic oligomers. More excitingly, the PNAMR@AuNCs were able to restore the natural unfolded conformation of hIAPP via dissolving the ß-sheet-rich hIAPP fibrils. Considering the uniform molecular mechanism of protein misfolding and fibrillation in conformation disorders, this finding provides a generic therapeutic strategy for neurodegenerative diseases and other conformation diseases by using PNAMR@AuNC artificial chaperones to restore and maintain the native conformation of amyloid proteins.

The role of microRNAs in neurodegenerative diseases: a review.

MicroRNAs (miRNAs) are non-coding RNAs which are essential post-transcriptional gene regulators in various neuronal degenerative diseases and playact a key role in these physiological progresses. Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, and, stroke, are seriously threats to the life and health of all human health and life kind. Recently, various studies have reported that some various miRNAs can regulate the development of neurodegenerative diseases as well as act as biomarkers to predict these neuronal diseases conditions. Endogenic miRNAs such as miR-9, the miR-29 family, miR-15, and the miR-34 family are generally dysregulated in animal and cell models. They are involved in regulating the physiological and biochemical processes in the nervous system by targeting regulating different molecular targets and influencing a variety of pathways. Additionally, exogenous miRNAs derived from homologous plants and defined as botanmin, such as miR2911 and miR168, can be taken up and transferred by other species to be and then act analogously to endogenic miRNAs to regulate the physiological and biochemical processes. This review summarizes the mechanism and principle of miRNAs in the treatment of some neurodegenerative diseases, as well as discusses several types of miRNAs which were the most commonly reported in diseases. These miRNAs could serve as a study provided some potential biomarkers in neurodegenerative diseases might be an ideal and/or therapeutic targets for neurodegenerative diseases. Finally, the role accounted of the prospective exogenous miRNAs involved in mammalian diseases is described. 1. Listing a large number of neural-related miRNAs and sorting out their pathways. 2. Classify and sort miRNAs according to their mechanism of action. 3. Demonstrating the effects of up-regulation or down-regulation of each miRNAs on the nervous system.

Nitric Oxide and Tumors: From Small-Molecule Donor to Combination Therapy.

As an important endogenous signaling molecule, nitric oxide (NO) is involved in various physiological and pathological activities in living organisms. It is proved that NO plays a critical role in tumor therapy, while the extremely short half-life and nonspecific distribution of NO greatly limit its further clinical applications. Thus, the past few decades have witnessed the progress made in conquering these shortcomings, including developing innovative NO donors, especially smart and multimodal nanoplatforms. These platforms can precisely control the spatiotemporal distribution of therapeutic agents in the organism, which make big differences in tumor treatment. Here current NO therapeutic mechanisms for cancer, NO donors from small molecules to smart-responsive nanodrug delivery platforms, and NO-based combination therapy are comprehensively reviewed, emphasizing outstanding breakthroughs in these fields and hoping to bring new insights into NO-based tumor treatments.

Recent advances in the intracellular delivery of macromolecule therapeutics.

Intracellular delivery of macromolecules is a critical procedure for biological research and drug discovery, including proteins, peptides, vaccines, antibodies and genes. The penetration of macromolecule therapeutics through the cell membrane to intracellular targets is a prerequisite for their biological activity, but most delivery systems rely on the endocytic pathway to enter the cell and confront an inability to escape from the lysosome. A profound understanding of the cellular internalization of transporting carriers can (i) optimize the design of drug delivery systems, (ii) maintain the biological activity of biomolecular drugs, (iii) improve the efficiency of intracellular macromolecule transport and release, (iv) bring new opportunities for the discovery of macromolecule therapeutics and treatment of refractory disease. This article summarizes the uptake pathway of intracellular delivery vehicles for macromolecule drugs, hoping to provide ideas and references for macromolecule therapeutics delivery systems.