A Conditionally Releasable “Do not Eat Me” CD47 Signal Facilitates Microglia‐Targeted Drug Delivery for the Treatment of Alzheimer's Disease

Efficient brain drug delivery has been a challenge in the treatment of Alzheimer's disease (AD) and other brain disorders as blood‐brain barrier (BBB) impedes most drugs to reach brain. To overcome this obstacle, a novel poly(lactic‐co‐glycolic acid) (PLGA) nanoparticle conjugated with CD47 extracellular domain via reactive oxygen species (ROS)‐responsive phenylborate ester bond exhibiting “do not eat me” signal and BBB penetrating peptide CRTIGPSVC (CRT) and microglia modulation agent Nec‐1s encapsulated in it is developed. The experimental results show that the designed nanoparticle efficiently increases its half‐life in blood circulation by preventing engulfment via phagocytes, and enhances its brain distribution by synergistic effect of CD47 and CRT. The high level of ROS in mouse brain releases CD47 from the nanoparticles and the resultant particles are effectively phagocytized by resident microglia. The engulfed Nec‐1s modulates pathological microglia to a beneficial state, which reduces Aβ burden, microgliosis and astrocytosis, decreases cytokine production and oxidative stress in the brains of AD mice, and finally attenuates cognition deficits and synapse loss. The results first demonstrate that the conditionally releasable “do not eat me” CD47 signal remarkably facilitates microglia‐targeted drug delivery and warrants further study to develop therapeutic agent for AD treatment.     

Biomimetic Nanoparticles as a Theranostic Tool for Traumatic Brain Injury

Traumatic brain injury (TBI) triggers both central and peripheral inflammatory responses. Existing pharmacological drugs are unable to effectively and quickly target the brain inflamed regions, setting up a major roadblock towards effective brain trauma treatments. Nanoparticles (NPs) have been used in multiple diseases as drug delivery tools with remarkable success due to their rapid diffusion and specificity in the target organ. Here, leukocyte-based biomimetic NPs are fabricated as a theranostic tool to directly access inflamed regions in a TBI mouse model. This NP systemic delivery is visualized using advanced in vivo imaging techniques, including intravital microscopy and in vivo imaging system. The results demonstrate selective targeting of NPs to the injured brain and increased NPs accumulation among the peripheral organs 24 h after TBI. Interestingly, increased microglial proliferation, decreased macrophage infiltration, and reduced brain lesion following the NPs treatments compared to sham vehicle-treated mice are also found. In summary, the results suggest that NPs represent a promising future theranostic tool for TBI treatment.     

Reactive Oxygen Species-Activated CO Versatile Nanomedicine with Innate Gut Immune and Microbiome Remodeling Effects for Treating Inflammatory Bowel Disease

Abnormal activation of the gut mucosal immune system and a highly dysregulated gut microbiota play essential roles in the progression of inflammatory bowel disease (IBD). The clinical treatment of IBD remains highly challenging, with first-line drugs showing limited efficacy and significant side effects. A reactive oxygen species (ROS)-activated CO versatile nanomedicine (CMPs) capable of remodeling the gut immune-microbiota microenvironment via potent anti-oxidant, anti-inflammatory, and antimicrobial effects is developed. CORM-401-loaded mannose-modified peptide dendrimer nanogel: CMPs preferentially congregate on the surface of damaged colon mucosa after rectal administration and are subsequently internalized by activated immune cells. CORM-401 can release numerous CO molecules in response to high ROS levels in cells and at the site of IBD, resulting in multiple therapeutic effects. In vitro and in vivo studies have demonstrated that CMPs scavenge ROS, suppress inflammatory responses, eliminate pathogens, and alleviate colitis in mouse models. RNA sequencing reveals that CMPs successfully remodel gut mucosal immune homeostasis by scavenging ROS, inhibiting NF-κB/p38MAPK, activating PI3K-Akt, and inhibiting HIF-1-induced glycolysis. 16S ribosomal RNA sequencing shows that CMPs can remodel the gut flora composition by restraining detrimental bacteria and augmenting beneficial bacteria. This study develops a promising and versatile nanomedicine for the management of IBD.     

Engineering a Therapy‐Induced “Immunogenic Cancer Cell Death” Amplifier to Boost Systemic Tumor Elimination

Immunogenic cancer cell death (ICD) is drawing worldwide attention as it allows dying cancer cells to regulate the host's anti‐tumor immune system and awaken immunosurveillance. Thus, effectively activating therapy‐induced ICD is of great clinical significance to raise systemic anti‐tumor immunity and eradicate post‐treatment/abscopal cancer tissues. Enhanced cytotoxic reactive oxygen species (ROS) generation in cancer therapy has been positively correlated to ICD induction, which inspires design of a therapy‐induced ICD amplifier. The nanohybrid amplifier (FeOOH@STA/Cu‐LDH) is devised based on Cu‐containing layered double hydroxide (Cu‐LDH), incorporating ROS inducer (FeOOH nanodots), ROS generation booster (Cu‐LDH for photothermal therapy), and heat shock protein inhibitor (STA). Treating 4T1 tumor cells with this amplifier translocates calreticulins (CRT, one of main ICD signals) on the surface of dying cancer cells, which achieves the maximum at fever‐type temperature (40–42 °C). To demonstrate immunotherapeutic efficacy of this nanohybrid, 4T1 tumor‐bearing mouse model is established with primary and abscopal tumors. Significantly, only one treatment with the ICD amplifier eradicates the primary tumor and inhibits the abscopal tumor growth upon fever‐type heating and induces more cytotoxic T lymphocytes in abscopal tumors and spleens after treatment for 1 week. This research thus provides a new insight into nanomaterial‐mediated tumor immunotherapy.     

A Melanin‐Based Natural Antioxidant Defense Nanosystem for Theranostic Application in Acute Kidney Injury

Acute kidney injury (AKI) is frequently associated with oxidative stress and causes high mortality annually in clinics. Nanotechnology‐mediated antioxidative therapy is emerging as a novel strategy for the treatment of AKI. Herein, a novel biomedical use of the endogenous biopolymer melanin as a theranostic natural antioxidant defense nanoplatform for AKI is reported. In this study, ultrasmall Mn²⁺‐chelated melanin (MMP) nanoparticles are easily prepared via a simple coordination and self‐assembly strategy, and further incorporated with polyethylene glycol (MMPP). In vitro experiments reveal the ability of MMPP nanoparticles to scavenge multiple toxic reactive oxygen species (ROS) and suppress ROS‐induced oxidative stress. Additionally, in vivo results from a murine AKI model demonstrate preferential renal uptake of MMPP nanoparticles and a subsequent robust antioxidative response with negligible side effects according to positron emission tomography/magnetic resonance (PET/MR) bimodal imaging and treatment assessment. These results indicate that the effectiveness of MMPP nanoparticles for treating AKI suggests the potential efficacy of melanin as a natural theranostic antioxidant nanoplatform for AKI, as well as other ROS‐related diseases.     

An Activity-Based Nanosensor for Minimally-Invasive Measurement of Protease Activity in Traumatic Brain Injury

Current screening and diagnostic tools for traumatic brain injury (TBI) have limitations in sensitivity and prognostication. Aberrant protease activity is a central process that drives disease progression in TBI and is associated with worsened prognosis, thus direct measurements of protease activity can provide more diagnostic information. In this study, a nanosensor is engineered to release a measurable signal into the blood and urine in response to activity from the TBI-associated protease calpain. Readouts from the nanosensor are designed to be compatible with ELISA and lateral flow assays, clinically-relevant assay modalities. In a mouse model of TBI, the nanosensor sensitivity is enhanced when ligands that target hyaluronic acid are added. In evaluation of mice with mild or severe injuries, the nanosensor identifies mild TBI with a higher sensitivity than the biomarker glial fibrillary acidic protein (GFAP). This nanosensor technology allows for measurement of TBI-associated proteases without the need to directly access brain tissue and has the potential to complement existing TBI diagnostic tools.     

In Situ Polymerized Hollow Mesoporous Organosilica Biocatalysis Nanoreactor for Enhancing ROS‐Mediated Anticancer Therapy

The combination of reactive oxygen species (ROS)‐involved photodynamic therapy (PDT) and chemodynamic therapy (CDT) holds great promise for enhancing ROS‐mediated cancer treatment. Herein, an in situ polymerized hollow mesoporous organosilica nanoparticle (HMON) biocatalysis nanoreactor is reported to integrate the synergistic effect of PDT/CDT for enhancing ROS‐mediated pancreatic ductal adenocarcinoma treatment. 2‐(1‐hexyloxyethyl)‐2‐devinylpyropheophorbide‐a photosensitizer is hybridized within the framework of HMON via an “in situ framework growth” approach. Then, the hollow cavity of HMONs is exploited as a nanoreactor for “in situ polymerization” to synthesize the polymer containing thiol groups, thereby enabling the immobilization of ultrasmall gold nanoparticles, which behave like glucose oxidase‐like nanozyme, converting glucose into H₂O₂ to provide self‐supplied H₂O₂ for CDT. Meanwhile, Cu²⁺‐tannic acid complexes are further deposited on the surface of HMONs (HMON‐Au@Cu‐TA) to initiate Fenton‐like reaction to covert the self‐supplied H₂O₂ into ?OH, a highly toxic ROS. Finally, collagenase (Col), which can degrade the collagen I fiber in the extracellular matrix, is loaded into HMON‐Au@Cu‐TA to enhance the penetration of HMONs and O₂ infiltration for enhanced PDT. This study provides a good paradigm for enhancing ROS‐mediated antitumor efficacy. Meanwhile, this research offers a new method to broaden the application of silica based nanotheranostics.     

Biocatalytic and Antioxidant Nanostructures for ROS Scavenging and Biotherapeutics

In human systems, reactive oxygen species (ROS) significantly affect different physiological activities and play critical roles in diverse living processes. It is widely known that excessive ROS generation in inflammatory tissues can further deteriorate the localized tissue injury and cause chronic diseases. Though promising for reducing ROS levels, many antioxidant molecules and natural enzymes suffer from abundant intrinsic limitations. Recently, a series of biocatalytic or antioxidant nanostructures have been designed with distinctive ROS scavenging capabilities, which show promising activities to overcome these kernel challenges. In this timely review, the most recent advances in engineering biocatalytic and antioxidant nanostructures for ROS scavenging are summarized. First, the ROS scavenging principles and corresponding methods for testing various enzymatic activities are carefully concluded. Subsequently, the rationally designed nanostructures with high ROS scavenging efficiencies are comprehensively discussed, especially on the catalytic activities, mechanisms, and structure-function relationships. After that, the representative applications of these ROS scavenging nanostructures for diverse biotherapeutics are summarized in detail. At last, the primary challenges and future perspectives in this emerging research frontier have also been outlined. It is believed that this progress review will offer a cutting-edge understanding and guidance to engineering future high-performance ROS scavenging nanostructures for broad biotherapeutic applications.     

Ultrasound‐Activated Oxygen and ROS Generation Nanosystem Systematically Modulates Tumor Microenvironment and Sensitizes Sonodynamic Therapy for Hypoxic Solid Tumors

Sonodynamic therapy (SDT) is noninvasive and possesses high body‐penetration depth, showing great potential for the treatment of deep‐seated solid tumors. The efficacy of SDT, however, is limited by widespread hypoxia in solid tumors. Given this, an ultrasound‐activated nanosystem is developed by integrating ferrate(VI) and protoporphyrin IX into biodegradable hollow mesoporous organosilica nanoplatforms, followed by assembling a phase‐change material of lauric acid. The ferrate(VI) effectively reacts with water as well as overexpressed hydrogen peroxide and glutathione (GSH) in tumor cells, leading to tumor‐microenvironment‐independent oxygen production and in situ GSH depletion in tumors. More importantly, significant reactive oxygen species (ROS) overproduction is simultaneously achieved by protoporphyrin‐augmented SDT and intracellular Fenton chemistry. Furthermore, the mild hyperthermia induced by ultrasound can trigger the phase change of lauric acid, achieving ultrasound‐responsive control over the release of oxygen and ROS, and the depletion of GSH. The simultaneous oxygen generation, in situ GSH depletion, and ROS overproduction play a synergetic role in sensitizing SDT toward hypoxic solid tumors, which is verified by the remarkable improvement of hypoxic environments and more significant growth inhibition of SDT against osteosarcoma both in vitro and in vivo, showing promising application in hypoxic solid tumor treatment.     

Fluorescent Gold Nanoprobe Sensitive to Intracellular Reactive Oxygen Species

Gold nanoprobes immobilized with fluorescein‐hyaluronic acid (HA) conjugates are fabricated and utilized for monitoring intracellular reactive oxygen species (ROS) generation in live cells via nanoparticle surface energy transfer. A bio‐inspired adhesive molecule, dopamine, is used to robustly end‐immobilize HA onto the surface of gold nanoparticles (AuNPs) for securing intracellular stability against glutathione. ROS induces cleavage and fragmentation of the HA chains immobilized on the surface of the AuNPs allows rapid and specific detection of intracellular ROS by emitting strong fluorescence‐recovery signals. In particular, fluorescence‐quenched gold nanoprobes exhibit selective and dose‐dependent fluorescence‐recovery signals upon exposure to certain oxygen species such as superoxide anion () and hydroxyl radical (^·OH). The fluorescent gold nanoprobe is usefully exploited for real‐time intracellular ROS detection and antioxidant screening assay, and has exciting potential for various biomedical applications as a new class of ROS imaging probes.     

Tumor Intracellular‐Environment Responsive Materials Shielded Nano‐Complexes for Highly Efficient Light‐Triggered Gene Delivery without Cargo Gene Damage

Gene therapy has great potential to bring tremendous improvement to cancer therapy. Recently, photochemical internalization (PCI) has provided the opportunity to overcome endo‐lysosomal sequestration, which is one of the main bottlenecks in both gene and chemotherapeutic delivery. Despite PCI having shown great potential in gene delivery systems, it still remains difficult to perform due to the photo‐oxidation of exogenous cargo genes by reactive oxygen species (ROS) generated from activated photosensitizers (PSs). In this paper, a new type of a stable light‐triggered gene delivery system is demonstrated based on endo‐lysosomal pH‐responsive polymeric PSs, which serve as shielding material for the polymer/gene complex. By taking advantage of the endo‐lysosomal pH‐sensitive de‐shielding ability of the pH‐responsive shielding material incorporated in the ternary gene complexes (pH‐TCs), a more significant photo‐triggered gene expression effect is achieved without damage to the gene from ROS. In contrast, pH‐insensitive material‐shielded nanocarriers cause photo‐oxidation of the payload and do not generate a notable transfection efficacy. Importantly, with the benefit of our newly developed gene delivery system, the deep penetration issue can be resolved. Finally, the light‐triggered gene delivery system using pH‐TCs is applied to deliver the therapeutic p53 gene in melanoma K‐1735 bearing mice, showing excellent therapeutic potential for cancer.     

Gold Nanocage‐Based Dual Responsive “Caged Metal Chelator” Release System: Noninvasive Remote Control with Near Infrared for Potential Treatment of Alzheimer's Disease

Metal ions have been demonstrated to participate in the pathology of Alzheimer's disease (AD): amyloid‐β peptide (Aβ) aggregation and formation of neurotoxic reactive oxygen species (ROS), such as H₂O₂. Metal chelator can block ROS formation and inhibit metal induced Aβ aggregation. Metal‐ion chelation therapy as a compelling treatment for AD has been extensively studied. However, most chelators are not suitable for AD treatment because of their poor permeability of the blood–brain barrier and their limited ability to differentiate toxic metals associated with Aβ plaques from those associated with normal metal homeostasis. Here, a novel dual‐responsive “caged metal chelator” release system based on gold nanocage (AuNC) for AD treatment is reported. Since arylboronic ester is redox‐ and thermal‐sensitive, phenylboronic acid‐functionalized AuNC can serve as an efficient delivery system for H₂O₂‐responsive controlled release of metal chelator. The release can be further enhanced through remote control with NIR light because of the high near‐infrared absorbance of AuNC. The smart system can effectively inhibit Aβ aggregate formation, decrease cellular ROS, and protect cells from Aβ‐related toxicity. In light of these advantages, this design provides new insights into noninvasive remote control with NIR to improve therapeutic efficacy for treatment of Alzheimer's disease.     

Bacterium‐Templated Polymer for Self‐Selective Ablation of Multidrug‐Resistant Bacteria

The recognition and inactivation of specific pathogenic bacteria remain an enormous scientific challenge and an important therapeutic goal. Therefore, materials that can selectively target and kill specific pathogenic bacteria, without harming beneficial strains are highly desirable. Here, a material platform is reported that exploits bacteria as a template to synthesize polymers with aggregation‐induced emission (AIE) characteristic by copper‐catalyzed atom transfer radical polymerization for self‐selective killing of the bacteria that templates them with no antimicrobial resistance. The bacteria‐templated polymers show very weak fluorescence in aqueous media, however, the fluorescence is turned on upon recognition of the bacteria used as the template to synthesize the polymer even at a low concentration of 600 ng mL^?1. Moreover, the incorporated AIE fluorogens (AIEgens) can act as an efficient photosensitizer for reactive oxygen species (ROS) generation after bacteria surface binding, which endows the templated polymers with the capability for selective bacterial killing. The bacterium‐templated synthesis is generally applicable to a wide range of bacteria, including clinically isolated multidrug‐resistant bacterial strains. It is envisioned that the bacterium‐templated method provides a new strategy for bacteria‐specific diagnostic and therapeutic applications.     

Assessment of Glial Fibrillary Acidic Protein Binding to the Surface of Leukocytes with Dark-Field Imaging and Computational Analysis

The glial fibrillary acidic protein (GFAP) is widely established as a traumatic brain injury (TBI) biomarker and can be used in early diagnosis. As essential primary human immune cells, leukocytes are recruited to injured cerebral sites during TBI response, where they can interact with and potentially bind to TBI biomarkers. To date, no studies have demonstrated ultra-low GFAP binding enumeration on leukocytes. Herein, a dark-field imaging technique coupled with computational analysis is introduced to quantify GFAP bound to peripheral blood mononuclear cells (PBMCs). Dark-field microscopy (DFM) with a custom-written image acquisition software is developed for rapid 3D PBMC imaging by utilizing specific antiGFAP monoclonal antibody functionalized gold nanoparticles (antiGFAP-AuNPs) as contrast-generating probes. Subsequently, the developed algorithm is utilized in processing thousands of acquired images for rapid visualization and enumeration of bound antiGFAP-AuNP on each leukocyte. The proposed method is demonstrates the specific binding of GFAP to the surface of PBMCs on a healthy donor blood. Thereafter, subpopulations of PBMCs with antiGFAP-AuNP binding are identified with the assistance of fluorescence imaging and DFM imaging, paving a new way to understanding the relationship between TBI and leukocyte classes. Hence, this study offers a rapid and ultra-sensitive strategy for biomarker assessment following TBI.     

A Fluorinated Bola‐Amphiphilic Dendrimer for On‐Demand Delivery of siRNA,via Specific Response to Reactive Oxygen Species

Functional materials capable of responding to stimuli intrinsic to diseases are extremely important for specific drug delivery at the disease site. However, developing on‐demand stimulus‐responsive vectors for targeted delivery is highly challenging. Here, a stimulus‐responsive fluorinated bola‐amphiphilic dendrimer is reported for on‐demand delivery of small interfering RNA (siRNA) in response to the characteristic high level of reactive oxygen species (ROS) in cancer cells. This dendrimer bears a ROS‐sensitive thioacetal in the hydrophobic core and positively charged poly(amidoamine) dendrons at the terminals, capable of interacting and compacting the negatively charged siRNA into nanoparticles to protect the siRNA and promote cellular uptake. The ROS‐sensitive feature of this dendrimer boosts specific and efficient disassembly of the siRNA/vector complexes in ROS‐rich cancer cells for effective siRNA delivery and gene silencing. Moreover, the fluorine tags in the vector enable ¹⁹F‐NMR analysis of the ROS‐responsive delivery process. In addition, this ingenious and distinct bola‐amphiphilic dendrimer is also able to combine the advantageous delivery features of both lipid and dendrimer vectors. Therefore, it represents an innovative on‐demand stimulus‐responsive delivery platform.     

Intranuclear Photosensitizer Delivery and Photosensitization for Enhanced Photodynamic Therapy with Ultralow Irradiance

Photodynamic therapy (PDT) is a well‐established clinical treatment modality for various diseases. However, reactive oxygen species (ROS) generated by photosensitizers(PS) under proper irradiation exhibits the extremely short life span (<200 ns) and severely limited diffusion distance (20 nm), so the damage of ROS to biomolecules, especially DNA, is strongly confined to the immediate vicinity of ROS generation. In this report, an efficient nuclear‐targeted delivery strategy is proposed by using TAT and RGD peptides co‐conjugated mesoporous silica nanoparticles (MSNs) as PS carriers. The conjugation of TAT peptides enable the nuclear penetration of MSNs for efficient accumulation of PS inside nuclei. The intranuclear‐accumulated PS can generate ROS upon irradiation right inside nuclei to destroy DNA instantaneously. For the purpose of in vivo applications, the co‐conjugated RGD peptides endow the nuclear‐targeted delivery system with specific binding and recognition to tumor vasculature and tumor cell membranes for significantly enhanced specificity and reduced side effects. Through intravenous injection of these nanosystems in tumor‐bearing mice at a rather low PS dose of 2 mg/kg, tumor growth is efficiently inhibited by an extremely low irradiation dose of 6 J/cm². This work presents a new paradigm for specific PDT with high efficacy and low side effects in vivo.     

大鼠中重度创伤性脑损伤后β-EP、CD4^＋、CD8^＋和IL-2的变化及其意义

目的：通过观察大鼠创伤性脑损伤后血浆β-EP、CD4^＋、CD8^＋和IL-2的动态变化,了解脑创伤后机体细胞免疫变化。方法：（1）采用气体冲击致大鼠中重度脑损伤模型;（2）流式细胞术检测血浆中CD4^＋、CD8^＋的含量;放射免疫法（RIA）测定血浆中β-EP的含量;酶联免疫吸附试验（ELISA）测血浆中IL-2的含量。结果：CD4^＋与IL-2含量在TBI后6h显著降低,CD4^＋和IL-2分别于1d、3d达到谷值;β-EP、CD8^＋6h显著升高,分别于6h、1d达到峰值。CD4^＋与IL-2呈直线正相关性;CD4^＋和IL-2降低,β-EP和CD8^＋升高,引起免疫平衡紊乱,表现为细胞免疫功能抑制。     

NIR/ROS‐Responsive Black Phosphorus QD Vesicles as Immunoadjuvant Carrier for Specific Cancer Photodynamic Immunotherapy

2D black phosphorus (BP) nanosheets and BP quantum dots (BPQD), as two main material styles of BP, are widely used in the biomedical filed. However, few stimuli‐responsive BP nanocarriers are reported to meet the need of nanomedicine. Herein, near‐infrared region/reactive oxygen species (NIR/ROS) sensitive BPQD vesicles (BPNVs) are prepared by self‐assembly of amphiphilic BPQDs grafted with polyethylene glycol and ROS sensitive poly(propylene sulfide) (PPS). BPNVs exhibit enhanced photo‐absorption in the NIR region, and have high loading efficiency of immunoadjuvant CpG oligodeoxynucleotides (CpG ODNs) in the cavity of the BPNVs. Upon NIR laser irradiation, high levels of ROS are generated from BPNVs to trigger the change of hydrophobic PPS to hydrophilic polymers, leading to disassembly of the vesicles to BPQDs. In this manner, the BPNVs show synergistic photodynamic therapy combined with immunotherapy, due to simultaneous release of small BPQDs with deep tumor penetration and CpG with enhanced immunotherapy. The BPNVs‐CpG achieves potent photodynamic immunotherapy in vivo, in addition to block distant tumor growth and metastasis.     

A Zn‐Doped CuO Nanocomposite Shows Enhanced Antibiofilm and Antibacterial Activities Against Streptococcus Mutans Compared to Nanosized CuO

Zinc‐doped copper oxide and copper oxide nanoparticles (NPs) are synthesized and deposited on artificial teeth by sonic irradiation, and the ability of these coatings to restrict biofilm formation by Streptococcus mutans is examined. The CuO and Zn:CuO NP‐coated teeth show significant reductions in biofilm formation of 70% and 88%, respectively, compared to uncoated teeth. The mechanism of the Zn:CuO nanoparticles is investigated, revealing that the nanoparticles attach to and penetrate the bacteria and generate intracellular reactive oxygen species (ROS) that enhance lipid peroxidation and cause cell death. Conversely, the CuO or ZnO NPs do not show this behavior and could not generate intracellular ROS. These results highlight the superior efficacy of Zn:CuO nanocomposites over CuO and ZnO NPs and the role of ROS in their antimicrobial effect.