A natural killer T cell nanoagonist-initiated immune cascade for hepatocellular carcinoma synergistic immunotherapy.

Natural killer T (NKT) cell-mediated immunotherapy shows great promise in hepatocellular carcinoma featuring an inherent immunosuppressive microenvironment. However, targeted delivery of NKT cell agonists remains challenging. Here, we developed a hyaluronic acid (HA) modified metal organic framework (zeolitic imidazolate framework-8, ZIF-8) to encapsulate α-galactosylceramide (α-Galcer), a classic NKT cell agonist, and doxorubicin (DOX) for eliminating liver cancer, denoted as α-Galcer/DOX@ZIF-8@HA. In the tumor microenvironment (TME), these pH-responsive nano-frameworks can gradually collapse to release α-Galcer for activating NKT cells and further boosting other immune cells in order to initiate an antitumor immune cascade. Along with DOX, the released α-Galcer enabled efficient NKT cell activation in TME for synergistic immunotherapy and tumor elimination, leading to evident tumor suppression and prolonged animal survival in both subcutaneous and orthotopic liver tumor models. Manipulating NKT cell agonists into functional nano-frameworks in TME may be matched with other advanced managements applied in a wider range of cancer therapies.

Traditional Chinese Medicine Formulae QY305 Reducing Cutaneous Adverse Reaction and Diarrhea by its Nanostructure.

Traditional Chinese medicine (TCM) is widely used in clinical practice, including skin and gastrointestinal diseases. Here, a potential TCM QY305 (T-QY305) is reported that can modulate the recruitment of neutrophil in skin and colon tissue thus reducing cutaneous adverse reaction and diarrhea induced by epidermal growth factor receptor inhibitors (EGFRIs). On another hand, the T-QY305 formula, through regulating neutrophil recruitment features would highlight the presence of N-QY305, a subunit nanostructure contained in T-QY305, and confirm its role as potentially being the biomaterial conferring to T-QY305 its pharmacodynamic features. Here, the clinical records of two patients are analyzed expressing cutaneous adverse reaction and demonstrate positive effect of T-QY305 on the simultaneous inhibition of both cutaneous adverse reaction and diarrhea in animal models. The satisfying results obtained from T-QY305, lead to further process to the isolation of N-QY305 from T-QY305, in order to demonstrate that the potency of T-QY305 originates from the nanostructure N-QY305. Compared to T-QY305, N-QY305 exhibits higher potency upon reducing adverse reactions. The data represent a promising candidate for reducing cutaneous adverse reaction and diarrhea, meanwhile proposing a new strategy to highlight the presence of nanostructures being the "King" of Chinese medicine formula as the pharmacodynamic basis.

Sulfur-Doped NiFe Hydroxide Nanobowls with Wrinkling Patterns for Photothermal Cancer Therapy.

Hierarchical multiscale wrinkling nanostructures have shown great promise for many biomedical applications, such as cancer diagnosis and therapy. However, synthesizing these materials with precise control remains challenging. Here, we report a sulfur doping strategy to synthesize sub-1 nm NiFe hydroxide ultrathin nanosheets (S-NiFe HUNs). The introduction of sulfur affects the reduction of the band gap and the adjustment of the electronic structure, thereby improving the light absorption ability of the S-NiFe HUNs. Additionally, S-NiFe HUNs show a multilayered nanobowl-like structure that enables multiple reflections of incident light inside the nanostructure, which improved the utilization of incident light and achieved high photothermal conversion. As a result, the as-prepared product with hydrophilic modification (dS-NiFe HUNs) demonstrated enhanced tumor-killing ability in vitro. In a mouse model of breast cancer, dS-NiFe HUNs combined with near-infrared light irradiation greatly inhibited tumor growth and prolonged the mice survival. Altogether, our study demonstrates the great potential of dS-NiFe HUNs for cancer photothermal therapy applications.

Suppression of cytokine release syndrome during CAR-T-cell therapy via a subcutaneously injected interleukin-6-adsorbing hydrogel.

The infusion of chimaeric antigen receptor (CAR) T cells can trigger the release of life-threatening supraphysiological levels of pro-inflammatory cytokines. However, uncertainty regarding the timing and severity of such cytokine release syndrome (CRS) demands careful monitoring of the conditions required for the administration of neutralizing antibodies. Here we show that a temperature-sensitive hydrogel conjugated with antibodies for the pro-inflammatory cytokine interleukin-6 (IL-6) and subcutaneously injected before the infusion of CAR-T cells substantially reduces the levels of IL-6 during CRS while maintaining the therapy's antitumour efficacy. In immunodeficient mice and in mice with transplanted human haematopoietic stem cells, the subcutaneous IL-6-adsorbing hydrogel largely suppressed CAR-T-cell-induced CRS, substantially improving the animals' survival and alleviating their levels of fever, hypotension and weight loss relative to the administration of free IL-6 antibodies. The implanted hydrogel, which can be easily removed with a syringe following a cooling-induced gel-sol transition, may allow for a shift in the management of CRS, from monitoring to prevention.

Conformation Dependent Architectures of Assembled Antimicrobial Peptides with Enhanced Antimicrobial Ability.

Antimicrobial peptides (AMPs) are a developing class of natural and synthetic oligopeptides with host defense mechanisms against a broad spectrum of microorganisms. With in-depth research on the structural conformations of AMPs, synthesis or modification of peptides has shown great potential in effectively obtaining new therapeutic agents with improved physicochemical and biological properties. Notably, AMPs with self-assembled properties have gradually become a hot research topic for various biomedical applications. Compared to monomeric peptides, these peptides can exist in diverse forms (e.g., nanoparticles, nanorods, and nanofibers) and possess several advantages, such as high stability, good biocompatibility, and potent biological functions, after forming aggregates under specific conditions. In particular, the stability and antibacterial property of these AMPs can be modulated by rationally regulating the peptide sequences to promote self-assembly, leading to the reconstruction of molecular structure and spatial orientation while introducing some peptide fragments into the scaffolds. In this work, four self-assembled AMPs are developed, and the relationship between their chemical structures and antibacterial activity is explored extensively through different experiments. Importantly, the evaluation of antibacterial performance in both in vitro and in vivo studies has provided a general guide for using self-assembled AMPs in subsequent treatments for combating bacterial infections.

DNA Damage Inducer Mitoxantrone Amplifies Synergistic Mild-Photothermal Chemotherapy for TNBC via Decreasing Heat Shock Protein 70 Expression.

Patients with triple-negative breast cancer (TNBC) have the worst clinical outcomes when compared to other subtypes of breast cancer. Nanotechnology-assisted photothermal therapy (PTT) opens new opportunities for precise cancer treatment. However, thermoresistance caused by PTT, as well as uncertainty in the physiological metabolism of existing phototherapeutic nanoformulations, severely limit their clinical applications. Herein, based on the clinically chemotherapeutic drug mitoxantrone (MTO), a multifunctional nanoplatform (MTO-micelles) is developed to realize mutually synergistic mild-photothermal chemotherapy. MTO with excellent near-infrared absorption (≈669 nm) can function not only as a chemotherapeutic agent but also as a photothermal transduction agent with elevated photothermal conversion efficacy (ƞ = 54.62%). MTO-micelles can accumulate at the tumor site through the enhanced permeability and retention effect. Following local near-infrared irradiation, mild hyperthermia (<50 °C) assists MTO in binding tumor cell DNA, resulting in chemotherapeutic sensitization. In addition, downregulation of heat shock protein 70 (HSP70) expression due to enhanced DNA damage can in turn weaken tumor thermoresistance, boosting the efficacy of mild PTT. Both in vitro and in vivo studies indicate that MTO-micelles possess excellent synergetic tumor inhibition effects. Therefore, the mild-photothermal chemotherapy strategy based on MTO-micelles has a promising prospect in the clinical transformation of TNBC treatment.

Navigations of the targeting pathway of nanomedicines toward tumor.

INTRODUCTION: Nanomedicines (NMs) have emerged as a promising approach for revolutionizing cancer treatment outcomes, mainly due to their benefits in the tumor-targeted delivery of therapeutics. The preferential accumulation of NMs in tumors has been widely verified by macroscopical technologies. Accordingly, several classic and emerging targeting mechanisms have been proposed to support the tumor-specific delivery of NMs. The targeting mechanism has been a topic of intense interest and controversy in the field of NMs development. Especially, the mechanisms by which NMs target tumor remain elusive. AREA COVERED: This topical review mainly discussed the evolution of the targeting mechanisms, crucial issues associated with each mechanism, and confused debates among the mechanisms. The targeting mechanisms of tumor-specific NMs discussed here include the enhanced permeability and retention (EPR) effect, protein corona-mediated targeting delivery, circulating cell mediated transportation, and transcytosis. EXPERT OPINION: It is of great significance for ultimate clinical translation to have more comprehensive considerations on the mechanism driving the pathway of NMs toward tumors. Our thoughts in this review are expected to provide a comprehensive understanding of the mechanisms and elicit thorough explorations of new mechanisms to renovate the knowledge framework of NMs delivery. [Figure: see text].

Functionalized Macrophage Exosomes with Panobinostat and PPM1D-siRNA for Diffuse Intrinsic Pontine Gliomas Therapy.

Diffuse intrinsic pontine glioma (DIPG) is a rare and fatal pediatric brain tumor. Mutation of p53-induced protein phosphatase 1 (PPM1D) in DIPG cells promotes tumor cell proliferation, and inhibition of PPM1D expression in DIPG cells with PPM1D mutation effectively reduces the proliferation activity of tumor cells. Panobinostat effectively kills DIPG tumor cells, but its systemic toxicity and low blood-brain barrier (BBB) permeability limits its application. In this paper, a nano drug delivery system based on functionalized macrophage exosomes with panobinostat and PPM1D-siRNA for targeted therapy of DIPG with PPM1D mutation is prepared. The nano drug delivery system has higher drug delivery efficiency and better therapeutic effect than free drugs. In vivo and in vitro experimental results show that the nano drug delivery system can deliver panobinostat and siRNA across the BBB and achieve a targeted killing effect of DIPG tumor cells, resulting in the prolonged survival of orthotopic DIPG mice. This study provides new ideas for the delivery of small molecule drugs and gene drugs for DIPG therapy.

Nanomaterials with changeable physicochemical property for boosting cancer immunotherapy.

The past decade has witnessed a great progress in cancer immunotherapy with the sequential approvals of therapeutic cancer vaccine, immune checkpoint inhibitor and chimeric antigen receptor (CAR) T cell therapy. However, some hurdles still remain to the wide implementation of cancer immunotherapy, including low immune response, complex tumor heterogeneity, off-target immunotoxicity, poor solid tumor infiltration, and immune evasion-induced treatment tolerance. Owing to changeable physicochemical properties in response to endogenous or exogenous stimuli, nanomaterials hold the remarkable potential in incorporation of multiple agents, efficient biological barrier penetration, precise immunomodulator delivery, and controllable content release for boosting cancer immunotherapy. Herein, we review the recent advances in nanomaterials with changeable physicochemical property (NCPP) to develop cancer vaccine, remold tumor microenvironment and evoke direct T cell activation. Besides, we provide our outlook on this emerging field at the intersection of NCPP design and cancer immunotherapy.

An amphiphilic dendrimer as a light-activable immunological adjuvant for in situ cancer vaccination.

Immunological adjuvants are essential for successful cancer vaccination. However, traditional adjuvants have some limitations, such as lack of controllability and induction of systemic toxicity, which restrict their broad application. Here, we present a light-activable immunological adjuvant (LIA), which is composed of a hypoxia-responsive amphiphilic dendrimer nanoparticle loaded with chlorin e6. Under irradiation with near-infrared light, the LIA not only induces tumour cell lysis and tumour antigen release, but also promotes the structural transformation of 2-nitroimidazole containing dendrimer to 2-aminoimidazole containing dendrimer which can activate dendritic cells via the Toll-like receptor 7-mediated signaling pathway. The LIA efficiently inhibits both primary and abscopal tumour growth and induces strong antigen-specific immune memory effect to prevent tumour metastasis and recurrence in vivo. Furthermore, LIA localizes the immunological adjuvant effect at the tumour site. We demonstrate this light-activable immunological adjuvant offers a safe and potent platform for in situ cancer vaccination.

Effect of physicochemical properties on in vivo fate of nanoparticle-based cancer immunotherapies.

Current advances of immunotherapy have greatly changed the way of cancer treatment. At the same time, a great number of nanoparticle-based cancer immunotherapies (NBCIs) have also been explored to elicit potent immune responses against tumors. However, few NBCIs are nearly in the clinical trial which is mainly ascribed to a lack understanding of in vivo fate of nanoparticles (NPs) for cancer immunotherapy. NPs for cancer immunotherapy mainly target the immune organs or immune cells to enable efficient antitumor immune responses. The physicochemical properties of NPs including size, shape, elasticity and surface properties directly affect their interaction with immune systems as well as their in vivo fate and therapeutic effect. Hence, systematic analysis of the physicochemical properties and their effect on in vivo fate is urgently needed. In this review, we first recapitulate the fundamentals for the in vivo fate of NBCIs including physio-anatomical features of lymphatic system and strategies to modulate immune responses. Moreover, we highlight the effect of physicochemical properties on their in vivo fate including lymph nodes (LNs) drainage, cellular uptake and intracellular transfer. Challenges and opportunities for rational design of NPs for cancer immunotherapy are also discussed in detail.

Flipped Quick-Response Code Enables Reliable Blood Grouping.

Accurate and rapid blood typing plays a vital role in a variety of biomedical and forensic scenarios, but recognizing weak agglutination remains challenging. Herein, we demonstrated a flipping identification with a prompt error-discrimination (FLIPPED) platform for automatic blood group readouts. Bromocresol green dye was exploited as a characteristic chromatography indicator for the differentiation of plasma from whole blood by presenting a teal color against a brown color. After integrating these color changes into a quick-response (QR) code, prompt typing of ABO and Rhesus groups was automatically achieved and data could be uploaded wirelessly within 30 s using a commercially available smartphone to facilitate blood cross-matching. We further designed a color correction model and algorithm to remove potential errors from scanning angles and ambient light intensities, by which weak agglutination could be accurately recognized. With comparable accuracy and repeatability to classical column assay in grouping 450 blood samples, the proposed approach further demonstrates to be a versatile sample-to-result platform for clinical diagnostics, food safety, and environmental monitoring.

Proton-driven transformable nanovaccine for cancer immunotherapy.

Cancer vaccines hold great promise for improved cancer treatment. However, endosomal trapping and low immunogenicity of tumour antigens usually limit the efficiency of vaccination strategies. Here, we present a proton-driven nanotransformer-based vaccine, comprising a polymer-peptide conjugate-based nanotransformer and loaded antigenic peptide. The nanotransformer-based vaccine induces a strong immune response without substantial systemic toxicity. In the acidic endosomal environment, the nanotransformer-based vaccine undergoes a dramatic morphological change from nanospheres (about 100 nanometres in diameter) into nanosheets (several micrometres in length or width), which mechanically disrupts the endosomal membrane and directly delivers the antigenic peptide into the cytoplasm. The re-assembled nanosheets also boost tumour immunity via activation of specific inflammation pathways. The nanotransformer-based vaccine effectively inhibits tumour growth in the B16F10-OVA and human papilloma virus-E6/E7 tumour models in mice. Moreover, combining the nanotransformer-based vaccine with anti-PD-L1 antibodies results in over 83 days of survival and in about half of the mice produces complete tumour regression in the B16F10 model. This proton-driven transformable nanovaccine offers a robust and safe strategy for cancer immunotherapy.

High-Fidelity Determination and Tracing of Small Extracellular Vesicle Cargoes.

Direct tracing of small extracellular vesicle (sEV) cargoes holds unprecedented importance for elucidating the mechanisms involved in intercellular communication. However, high-fidelity determination of sEVs' molecular cargoes in situ has yet to be achieved due to the difficulty in transporting molecular probes into intact sEVs. Herein, a fLuorescent Intracellular-Guided Hairpin-Tetrahedron (fLIGHT) nanoprobe is described for direct visualization of sEV microRNAs in situ. Integrating the advantages of nondestructive sEV penetration via DNA origami and single-nucleotide discrimination as well as wash-free fluorescence readout using a hairpin probe, the proposed approach enables high-fidelity fluorescence visualization of sEVs' microRNA without RNA extraction or leakage, demonstrating the potential of on-site tracing of sEV cargoes. This strategy opens an avenue to establishing universal molecular detection and labeling platforms that can facilitate both sEV-derived fundamental biological studies and molecular diagnostics.

Rolling Circular Amplification (RCA)-Assisted CRISPR/Cas9 Cleavage (RACE) for Highly Specific Detection of Multiple Extracellular Vesicle MicroRNAs.

Multiplexed detection of extracellular vesicle (EV)-derived microRNAs (miRNAs) plays a critical role in facilitating disease diagnosis and prognosis evaluation. Herein, we developed a highly specific nucleic acid detection platform for simultaneous quantification of several EV-derived miRNAs in constant temperature by integrating the advantages of a clustered regularly interspaced short palindromic repeats/CRISPR associated nucleases (CRISPR/Cas) system and rolling circular amplification (RCA) techniques. Particularly, the proposed approach demonstrated single-base resolution attributed to the dual-specific recognition from both padlock probe-mediated ligation and protospacer adjacent motif (PAM)-triggered cleavage. The high consistency between the proposed approach RCA-assisted CRISPR/Cas9 cleavage (RACE) and reverse transcription quantitative polymerase chain reaction (RT-qPCR) in detecting EV-derived miRNAs' abundance from both cultured cancer cells and clinical lung cancer patients validated its robustness, revealing its potentials in the screening, diagnosis, and prognosis of various diseases. In summary, RACE is a powerful tool for multiplexed, specific detection of nucleic acids in point-of-care diagnostics and field-deployable analysis.

Thermo-responsive triple-function nanotransporter for efficient chemo-photothermal therapy of multidrug-resistant bacterial infection.

New strategies with high antimicrobial efficacy against multidrug-resistant bacteria are urgently desired. Herein, we describe a smart triple-functional nanostructure, namely TRIDENT (Thermo-Responsive-Inspired Drug-Delivery Nano-Transporter), for reliable bacterial eradication. The robust antibacterial effectiveness is attributed to the integrated fluorescence monitoring and synergistic chemo-photothermal killing. We notice that temperature rises generated by near-infrared irradiation did not only melt the nanotransporter via a phase change mechanism, but also irreversibly damaged bacterial membranes to facilitate imipenem permeation, thus interfering with cell wall biosynthesis and eventually leading to rapid bacterial death. Both in vitro and in vivo evidence demonstrate that even low doses of imipenem-encapsulated TRIDENT could eradicate clinical methicillin-resistant Staphylococcus aureus, whereas imipenem alone had limited effect. Due to rapid recovery of infected sites and good biosafety we envision a universal antimicrobial platform to fight against multidrug-resistant or extremely drug-resistant bacteria.