Design of Ultrasound-Driven Charge Interference Therapy for Wound Infection.

Wound infections, especially those caused by pathogenic bacteria, present a considerable public health concern due to associated complications and poor therapeutic outcomes. Herein, we developed antibacterial nanoparticles, namely, PGTP, by coordinating guanidine derivatives with a porphyrin-based sonosensitizer. The synthesized PGTP nanoparticles, characterized by their strong positive charge, effectively disrupted the bacterial biosynthesis process through charge interference, demonstrating efficacy against both Gram-negative and Gram-positive bacteria. Additionally, PGTP nanoparticles generated reactive oxygen species under ultrasound stimulation, resulting in the disruption of biofilm integrity and efficient elimination of pathogens. RNA-seq analysis unveiled the detailed mechanism of wound healing, revealing that PGTP nanoparticles, when coupled with ultrasound, impair bacterial metabolism by interfering with the synthesis and transcription of amino acids. This study presents a novel approach to combatting wound infections through ultrasound-driven charge-interfering therapy, facilitated by advanced antibacterial nanomaterials.

Bimetallic Nanoplatforms for Prostate Cancer Treatment by Interfering Cellular Communication.

Cellular communication mediated by messenger molecules plays an important role in the progression of cancer. Herein, pH-sensitive zeolitic imidazolate framework-8 (ZIF-8) loaded with PtCl2(OH)2(NH3)2 [i.e., Pt(IV)] bimetallic nanoplatforms were developed for prostate cancer therapy by interfering inositol-1, 4, 5-trisphosphate (IP3)-mediated cellular communication. As an important messenger in cells, the function of IP3 was found to be efficiently interfered with by the Pt(IV)-binding inositol unit. This finding effect of Pt(IV) is totally different from its traditional function as a prodrug of cis-platinum for chemotherapy. The decreased IP3 signal further downregulated the cytoplasmic Ca2+ concentration and downstream signal transduction to inhibit proliferation and invasion of tumor cells. Meanwhile, Zn2+ released from ZIF-8 under an acidic tumor microenvironment decreased adenosine triphosphate biosynthesis, which could further limit the cellular communication. Such a proposed strategy of interfering cellular communication has demonstrated its feasibility in this study, which may provide new perspectives for cancer therapy.

Anti-inflammatory and anti-oxidative electrospun nanofiber membrane promotes diabetic wound healing via macrophage modulation.

BACKGROUND: In the inflammatory milieu of diabetic chronic wounds, macrophages undergo substantial metabolic reprogramming and play a pivotal role in orchestrating immune responses. Itaconic acid, primarily synthesized by inflammatory macrophages as a byproduct in the tricarboxylic acid cycle, has recently gained increasing attention as an immunomodulator. This study aims to assess the immunomodulatory capacity of an itaconic acid derivative, 4-Octyl itaconate (OI), which was covalently conjugated to electrospun nanofibers and investigated through in vitro studies and a full-thickness wound model of diabetic mice. RESULTS: OI was feasibly conjugated onto chitosan (CS), which was then grafted to electrospun polycaprolactone/gelatin (PG) nanofibers to obtain P/G-CS-OI membranes. The P/G-CS-OI membrane exhibited good mechanical strength, compliance, and biocompatibility. In addition, the sustained OI release endowed the nanofiber membrane with great antioxidative and anti-inflammatory activities as revealed in in vitro and in vivo studies. Specifically, the P/G-CS-OI membrane activated nuclear factor-erythroid-2-related factor 2 (NRF2) by alkylating Kelch-like ECH-associated protein 1 (KEAP1). This antioxidative response modulates macrophage polarization, leading to mitigated inflammatory responses, enhanced angiogenesis, and recovered re-epithelization, finally contributing to improved healing of mouse diabetic wounds. CONCLUSIONS: The P/G-CS-OI nanofiber membrane shows good capacity in macrophage modulation and might be promising for diabetic chronic wound treatment.

Magnetic resonance imaging with upconversion nanoprobes capable of crossing the blood-cerebrospinal fluid barrier.

The central nervous system (CNS) maintains homeostasis with its surrounding environment by restricting the ingress of large hydrophilic molecules, immune cells, pathogens, and other external harmful substances to the brain. This function relies heavily on the blood-cerebrospinal fluid (B-CSF) and blood-brain barrier (BBB). Although considerable research has examined the structure and function of the BBB, the B-CSF barrier has received little attention. Therapies for disorders associated with the central nervous system have the potential to benefit from targeting the B-CSF barrier to enhance medication penetration into the brain. In this study, we synthesized a nanoprobe ANG-PEG-UCNP capable of crossing the B-CSF barrier with high targeting specificity using a hydrocephalus model for noninvasive magnetic resonance ventriculography to understand the mechanism by which the CSF barrier may be crossed and identify therapeutic targets of CNS diseases. This magnetic resonance nanoprobe ANG-PEG-UCNP holds promising potential as a safe and effective means for accurately defining the ventricular anatomy and correctly locating sites of CSF obstruction.

Regulating electron transportation by tungsten oxide nanocapacitors for enhanced radiation therapy.

In the process of radiation therapy (RT), the cytotoxic effects of excited electrons generated from water radiolysis tend to be underestimated due to multiple biochemical factors, particularly the recombination between electrons and hydroxyl radicals (·OH). To take better advantage of radiolytic electrons, we constructed WO3 nanocapacitors that reversibly charge and discharge electrons to regulate electron transportation and utilization. During radiolysis, WO3 nanocapacitors could contain the generated electrons that block electron-·OH recombination and contribute to the yield of ·OH at a high level. These contained electrons could be discharged from WO3 nanocapacitors after radiolysis, resulting in the consumption of cytosolic NAD+ and impairment of NAD+-dependent DNA repair. Overall, this strategy of nanocapacitor-based radiosensitization improves the radiotherapeutic effects by increasing the utilization of radiolytic electrons and ·OH, warranting further validation in multiple tumour models and preclinical experiments.

Flexible multilevel nonvolatile biocompatible memristor with high durability.

Current protein or glucose based biomemristors have low resistance-switching performance and require complex structural designs, significantly hindering the development of implantable memristor devices. It is imperative to discover novel candidate materials for biomemristor with high durability and excellent biosafety for implantable health monitoring. Herein, we initially demonstrate the resistance switching characteristics of a nonvolatile memristor in a configuration of Pt/AlOOH/ITO consisting of biocompatible AlOOH nanosheets sandwiched between a Indium Tin Oxides (ITO) electrode and a platinum (Pt) counter-electrode. The hydrothermally synthesized AlOOH nanosheets have excellent biocompatibility as confirmed through the Cell Counting Kit-8 (CCK-8) tests. Four discrete resistance levels are achieved in this assembled device in responsible to different compliance currents (ICC) for the set process, where the emerging multilevel states show high durability over 103 cycles, outperforming the protein-based biomemristors under similar conditions. The excellent performance of the Pt/AlOOH/ITO memristor is attributed to the significant role of hydrogen proton with pipe effect, as confirmed by both experimental results and density functional theory (DFT) analyses. The present results indicate the nonvolatile memristors with great potential as the next generation implantable multilevel resistive memories for long-term human health monitoring.

Acid Neutralization and Immune Regulation by Calcium-Aluminum-Layered Double Hydroxide for Osteoporosis Reversion.

Osteoporosis is a kind of global chronic bone disease characterized by progressive loss of bone mass and bone quality reduction, leading to a largely increased risk of bone fragility. In clinics, the current treatment of osteoporosis relies on the inhibition of bone damage by osteoclasts but ignores the function of immune cells in the progress of osteoporosis, leading to much compromised therapeutic efficacy. In this work, a highly effective osteoporosis-immunotherapeutic modality is established for the treatment of osteoporosis based on acid neutralization in synergy with immune microenvironment regulation by a specially designed nanocatalytic medicine, calcein functionalized calcium-aluminum-layered double hydroxide (CALC) nanosheets. Briefly, the mildly alkaline CALC nanosheets could neutralize the acidic microenvironment of osteoporosis accompanying the acidity-responsive LDH degradation. Subsequently, calcium phosphate nanoparticles (CAPs) are generated by the reaction between the released Ca2+ from LDH degradation and endogenous phosphates, resulting in M2 phenotype anti-inflammatory differentiation of bone macrophages through a c-Maf transcriptional factor pathway and the following activity enhancements of regulatory T cells (Treg) and the deactivation of T helper 17 cells (TH17). Both in vitro and in vivo results show an excellent therapeutic efficacy on osteoporosis featuring a significant BV/TV (%) enhancement of femurs from 6.2 to 10.7, demonstrating high feasibility of this therapeutic concept through the combined acid neutralization and immune regulation. Such an inorganic nanomaterial-based strategy provides a novel, efficient, and biosafe therapeutic modality for intractable osteoporosis treatment, which will benefit patients suffering from osteoporosis.

Lactic acid modified rare earth-based nanomaterials for enhanced radiation therapy by disturbing the glycolysis.

Deficient deposition of X-rays and strong capacity of repairing damage DNA of cancer cells limit the effect of radiation therapy (RT). Herein, we synthesize CsLu2F7 nanoparticles with lactic acid (LA) ligands (CsLu2F7-LA) to overcome these limitations. The high-Z atoms of Lu and Cs can deposit more X-rays for generating enhanced hydroxyl radicals (·OH). Meanwhile, the LA ligand will guide CsLu2F7-LA to target monocarboxylic acid transporter (MCT) and impede the transportation of free LA, leading to decreased glycolysis and DNA damage repair. Consequently, the curative effect of RT will be enhanced and the strategy of LA accumulation induced radiosensitization is proved by in vivo and in vitro experiments, which will bring prospects for enhanced RT with nanomedicine.

A novel antibacterial and antifouling nanocomposite coated endotracheal tube to prevent ventilator-associated pneumonia.

BACKGROUND: The endotracheal tube (ETT) is an essential medical device to secure the airway patency in patients undergoing mechanical ventilation or general anesthesia. However, long-term intubation eventually leads to complete occlusion, ETTs potentiate biofilm-related infections, such as ventilator-associated pneumonia. ETTs are mainly composed of medical polyvinyl chloride (PVC), which adheres to microorganisms to form biofilms. Thus, a simple and efficient method was developed to fabricate CS-AgNPs@PAAm-Gelatin nanocomposite coating to achieve dual antibacterial and antifouling effects. RESULTS: The PAAm-Gelatin (PAAm = polyacrylamide) molecular chain gel has an interpenetrating network with a good hydrophilicity and formed strong covalent bonds with PVC-ETTs, wherein silver nanoparticles were used as antibacterial agents. The CS-AgNPs@PAAm-Gelatin coating showed great resistance and antibacterial effects against Staphylococcus aureus and Pseudomonas aeruginosa. Its antifouling ability was tested using cell, protein, and platelet adhesion assays. Additionally, both properties were comprehensively evaluated using an artificial broncho-lung model in vitro and a porcine mechanical ventilation model in vivo. These remarkable results were further confirmed that the CS-AgNPs@PAAm-Gelatin coating exhibited an excellent antibacterial capacity, an excellent stain resistance, and a good biocompatibility. CONCLUSIONS: The CS-AgNPs@PAAm-Gelatin nanocomposite coating effectively prevents the occlusion and biofilm-related infection of PVC-ETTs by enhancing the antibacterial and antifouling properties, and so has great potential for future clinical applications.

High relaxivity Gd3+-based organic nanoparticles for efficient magnetic resonance angiography.

Contrast-enhanced MR angiography (MRA) is a critical technique for vascular imaging. Nevertheless, the efficacy of MRA is often limited by the low rate of relaxation, short blood-circulation time, and metal ion-released potential long-term toxicity of clinical available Gd-based contrast agents. In this work, we report a facile and efficient strategy to achieve Gd-chelated organic nanoparticles with high relaxivity for T1-weighted MRA imaging. The Gd-chelated PEG-TCPP nanoparticles (GPT NPs) have been engineered composite structured consisting of Gd-chelated TCPP and PEG. The spherical structure of TCPP offers more chemical sites for Gd3+ coordination to improve the relaxivity and avoid leakage of the Gd3+ ions. The synthesized GPT NPs exhibit a high relaxation rate of 35.76 mM- 1 s- 1 at 3.0 T, which is higher than the rates for most reported MR contrast agents. Therefore, GPT NPs can be used for MRA with much stronger vascular signals, longer circulation time, and high-resolution arterial vascular visualization than those using clinical MR contrast agents at the same dose. This work may make the T1 MRI contrast agents for high-resolution angiography possible and offer a new candidate for preclinical and clinical applications of MR vascular imaging and vascular disease diagnosis.

Ultrasmall Porous Silica Nanoparticles with Enhanced Pharmacokinetics for Cancer Theranostics.

Theranostic nanoparticles hold the potential to greatly improve cancer management by providing personalized medicine. Although many theranostic nanoconstructs have been successful in preclinical studies, clinical translation is still hampered by their limited targeting capability and lack of successful therapeutic efficacy. We report the use of novel ultrasmall porous silica nanoparticles (UPSN) with enhanced in vivo pharmacokinetics such as high target tissue accumulation (12% ID/g in the tumor) and evasion from the reticuloendothelial system (RES) organs. Herein, UPSN is conjugated with the isotopic pair 90/86Y, enabling both noninvasive imaging as well as internal radiotherapy. In vivo PET imaging demonstrates prolonged blood circulation and excellent tumor contrast with 86Y-DOTA-UPSN. Tumor-to-muscle and tumor-to-liver uptake values were significantly high (12.4 ± 1.7 and 1.5 ± 0.5, respectively), unprecedented for inorganic nanomaterials. 90Y-DOTA-UPSN significantly inhibits tumor growth and increases overall survival, indicating the promise of UPSN for future clinical translation as a cancer theranostic agent.

Nanomedicines for Renal Management: From Imaging to Treatment.

Nanomedicine has benefited from recent advances in chemistry and biomedical engineering to produce nanoscale materials as theranostic agents. Well-designed nanomaterials may present optimal biological properties, influencing circulation, retention, and excretion for imaging and treatment of various diseases. As the understanding of nanomedicine pharmacokinetics expands continuously, efficient renal clearance of nanomedicines can significantly increase the signal-to-background ratio for precision diagnosis and lower potential toxicity for improved treatment. Studies on nanomaterial-kidney interactions have led to many novel findings on the underlying principles of nanomaterial renal clearance, targeting, and accumulation. In return, the optimized nanomedicines confer significant benefits to the detection and treatment of kidney dysfunction.In this Account, we present an overview of recent progress in the development of nanomaterials for kidney theranostics, aiming to speed up translation and expand possible applications. We start by introducing biological structures of the kidney and their influence on renal targeting, retention, and clearance. Several key factors regarding renal accumulation and excretion, including nanomaterial types, sizes, and shapes, surface charges, and chemical modifications, are identified and discussed. Next, we highlight our recent efforts investigating kidney-interacting nanomaterials and introduce representative nanomedicines for imaging and treatment of kidney diseases. Multiple renal-clearable and renal-accumulating nanomedicines were devised for kidney function imaging. By employing renal-clearable nanomedicines, including gold nanoparticles, porphyrin polymers, DNA frameworks, and polyoxometalate clusters, we were able to noninvasively evaluate split renal function in healthy and diseased mice. Further engineering of renal-accumulating nanosystems has shifted attention from renal diagnosis to precision kidney protection. Many biocompatible nanomedicines, such as DNA origami, selenium-doped carbon quantum dots, melanin nanoparticles, and black phosphorus have all played essential roles in diminishing excessive reactive oxygen species for kidney treatment and protection. Finally, we discuss the challenges and perspectives of nanomaterials for renal care, their future clinical translation, and how they may affect the current landscape of clinical practices. We believe that this Account updates our current understanding of nanomaterial-kidney interactions for further design and control of nanomedicines for specific kidney diagnosis and treatment. This timely Account will generate broad interest in integrating nanotechnology and nanomaterial-biological interaction for state-of-the-art theranostics of renal diseases.

Antioxidant and C5a-blocking strategy for hepatic ischemia-reperfusion injury repair.

BACKGROUND: Nonspecific liver uptake of nanomaterials after intravenous injection has hindered nanomedicine for clinical translation. However, nanomaterials' propensity for liver distribution might enable their use in hepatic ischemia-reperfusion injury (IRI) repair. During hepatic IRI, reactive oxygen species (ROS) are generated and the fifth component of complement (C5a) is activated. In addition, C5a is confirmed to exacerbate the vicious cycle of oxidative stress and inflammatory damage. For these reasons, we have investigated the development of nanomaterials with liver uptake to scavenge ROS and block C5a for hepatic IRI repair. RESULTS: To achieve this goal, a traditional nanoantioxidant of nanoceria was surface conjugated with the anti-C5a aptamers (Ceria@Apt) to scavenge the ROS and reduce C5a-mediated inflammation. High uptake of Ceria@Apt in the liver was confirmed by preclinical positron emission tomography (PET) imaging. The clinical symptoms of hepatic IRI were effectively alleviated by Ceria@Apt with ROS scavenging and C5a blocking in mice model. The released pro-inflammatory cytokines were significantly reduced, and subsequent inflammatory reaction involved in the liver was inhibited. CONCLUSIONS: The synthesized Ceria@Apt has great potential of medical application in hepatic IRI repair, which could also be applied for other ischemic-related diseases.

Second near-infrared photothermal-amplified immunotherapy using photoactivatable composite nanostimulators.

BACKGROUND: The construction of a nanoimmune controlled-release system that spatiotemporally recognizes tumor lesions and stimulates the immune system response step by step is one of the most potent cancer treatment strategies for improving the sensitivity of immunotherapy response. RESULTS: Here, a composite nanostimulator (CNS) was constructed for the release of second near-infrared (NIR-II) photothermal-mediated immune agents, thereby achieving spatiotemporally controllable photothermal-synergized immunotherapy. CNS nanoparticles comprise thermosensitive liposomes as an outer shell and are internally loaded with a NIR-II photothermal agent, copper sulfide (CuS), toll-like receptor-9 (TLR-9) agonist, cytosine-phospho-guanine oligodeoxynucleotides, and programmed death-ligand 1 (PD-L1) inhibitors (JQ1). Following NIR-II photoirradiation, CuS enabled the rapid elevation of localized temperature, achieving tumor ablation and induction of immunogenic cell death (ICD) as well as disruption of the lipid shell, enabling the precise release of two immune-therapeutical drugs in the tumor region. Combining ICD, TLR-9 stimulation, and inhibited expression of PD-L1 allows the subsequent enhancement of dendritic cell maturation and increases infiltration of cytotoxic T lymphocytes, facilitating regional antitumor immune responses. CONCLUSION: CNS nanoparticle-mediated photothermal-synergized immunotherapy efficiently suppressed the growth of primary and distant tumors in two mouse models and prevented pulmonary metastasis. This study thus provides a novel sight into photo-controllably safe and efficient immunotherapy.

Efficient Gene Therapy of Pancreatic Cancer via a Peptide Nucleic Acid (PNA)-Loaded Layered Double Hydroxides (LDH) Nanoplatform.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignant tumors with extremely poor prognosis due to the later stage diagnosis when surgical resection is no longer applicable. Alternatively, the traditional gene therapy which drives pancreatic cancer cells into an inactive state and inhibiting the proliferation and metastasis, presents potentials to safely inhibit pancreatic cancer progression, but unfortunately has received limited success to date. Here, an efficient gene therapy of pancreatic cancer is shown via a peptide nucleic acid (PNA)-loaded layered double hydroxides (LDHs) nanoplatform. Compared with the traditional DNA- or RNA-based gene therapies, the gene therapy using PNA features great advantages in recognizing and hybridizing with the target mutant sequences to form PNA-DNA hybrids with significantly enhanced stability due to the absence of electrostatic repulsion, and the constrained flexibility of the polyamide backbone. Moreover, ultrasmall LDHs are engineered to load PNA and the obtained PNA-loaded LDH platform (LDHs/PNA) is capable of efficiently and selectively targeting the intranuclear mutant sequences thanks to the proton sponge effect. Treatments with LDHs/PNA demonstrate markedly inhibited growth of pancreatic cancer xenografts via a cancer cell proliferation suppression mechanism. The results demonstrate the great potentials of LDHs/PNA as a highly promising gene therapy agent for PDAC.

86/90Y-Labeled Monoclonal Antibody Targeting Tissue Factor for Pancreatic Cancer Theranostics.

Pancreatic cancer is highly aggressive, with a median survival time of less than 6 months and a 5-year overall survival rate of around 7%. The poor prognosis of PaCa is largely due to its advanced stage at diagnosis and the lack of efficient therapeutic options. Thus, the development of an efficient, multifunctional PaCa theranostic system is urgently needed. Overexpression of tissue factor (TF) has been associated with increased tumor growth, angiogenesis, and metastasis in many malignancies, including pancreatic cancer. Herein, we propose the use of a TF-targeted monoclonal antibody (ALT836) conjugated with the pair 86/90Y as a theranostic agent against pancreatic cancer. For methods, serial PET imaging with 86Y-DTPA-ALT836 was conducted to map the biodistribution the tracer in BXPC-3 tumor-bearing mice. 90Y-DTPA-ALT836 was employed as a therapeutic agent that also allowed tumor burden monitoring through Cherenkov luminescence imaging. The results were that the uptake of 86Y-DTPA-ALT836 in BXPC-3 xenograft tumors was high and increased over time up to 48 h postinjection (p.i.), corroborated through ex vivo biodistribution studies and further confirmed by Cherenkov luminescence Imaging. In therapeutic studies, 90Y-DTPA-ALT836 was found to slow tumor growth relative to the control groups and had significantly smaller (p < 0.05) tumor volumes 1 day p.i. Histological analysis of ex vivo tissues revealed significant damage to the treated tumors. The conclusion is that the use of the 86/90Y theranostic pair allows PET imaging with excellent tumor-to-background contrast and treatment of TF-expressing pancreatic tumors with promising therapeutic outcomes.

Alpha lipoic acid antagonizes cytotoxicity of cobalt nanoparticles by inhibiting ferroptosis-like cell death.

As a main element in the hard metal industry, cobalt is one of the major components of human metal implants. Cobalt-containing implants, especially joint prostheses used for artificial joint replacement, can be corroded due to the complex physiological environment in vivo, producing a large number of nanoscale cobalt particles (Cobalt Nanoparticles, CoNPs). These CoNPs can be first accumulated around the implant to cause adverse local reactions and then enter into the blood vessels followed by reaching the liver, heart, brain, kidney, and other organs through systematic circulation, which leads to multi-system toxicity symptoms. To ensure the long-term existence of cobalt-containing implants in the body, it is urgently required to find out a safe and effective detoxification drug. Herein, we have demonstrated that CoNPs could induce the ferroptosis-like cell death through the enhancement of intracellular reactive oxygen species (ROS) level, cytoplasmic Fe2+ level, lipid peroxidation, and consumption of reduced glutathione (GSH) as well as inhibition of glutathione peroxidase 4 (GPX4) activity. Importantly, α-lipoic acid (ALA), a natural antioxidant with the capability to scavenge free radicals and chelate toxic metals, was found to efficiently alleviate the adverse effects of CoNPs. The present study illustrates a new mechanism of CoNPs mediated by ferroptosis-like cytotoxicity and discloses an effective method for the detoxification of CoNPs by employing the natural antioxidant of ALA, providing a basis for further in vivo detoxification study.

Nanozyme: new horizons for responsive biomedical applications.

Nanozymes are nanomaterial-based artificial enzymes. By effectively mimicking catalytic sites of natural enzymes or harboring multivalent elements for reactions, nanozyme systems have successfully served as direct surrogates of traditional enzymes for catalysis. With the rapid development and ever-deepening understanding of nanotechnology, nanozymes offer higher catalytic stability, ease of modification and lower manufacturing cost than protein enzymes. Additionally, nanozymes possess inherent nanomaterial properties, providing not only a simple substitute of enzymes but also a multimodal platform interfacing complex biologic environments. Recent extensive research has focused on designing various nanozyme systems that are responsive to one or multiple substrates by tailored means. Catalytic activities of nanozymes can be regulated by pH, H2O2 and glutathione concentrations and levels of oxygenation in different microenvironments. Moreover, nanozymes can be remotely-controlled via different stimuli, including a magnetic field, light, ultrasound, and heat. Collectively, these factors can be adjusted to maximize the diagnostic and therapeutic efficacies of different diseases in biomedical settings. Therefore, by integrating the catalytic property and inherent nanomaterial nature of nanozyme systems, we anticipate that stimuli-responsive nanozymes will open up new horizons for diagnosis, treatment, and theranostics.

Aptamer-Conjugated Framework Nucleic Acids for the Repair of Cerebral Ischemia-Reperfusion Injury.

Effective therapy for protecting dying neurons against cerebral ischemia-reperfusion injury (IRI) represents a substantial challenge in the treatment of ischemic strokes. Oxidative stress coupled with excessive inflammation is the main culprit for brain IRI that results in neuronal damage and disability. Specifically, complement component 5a (C5a) exacerbates the vicious cycle between oxidative stress and inflammatory responses. Herein, we propose that a framework nucleic acid (FNA) conjugated with anti-C5a aptamers (aC5a) can selectively reduce C5a-mediated neurotoxicity and effectively alleviate oxidative stress in the brain. Intrathecal injection of the aC5a-conjugated FNA (aC5a-FNA) was applied for the treatment of rats with ischemic strokes. Positron emission tomography (PET) imaging was performed to investigate the accumulation of aC5a-FNA in the penumbra and its therapeutic efficacy. Results demonstrated that aC5a-FNA could rapidly penetrate different brain regions after brain IRI. Furthermore, aC5a-FNA effectively protected neurons from brain IRI, as verified by serum tests, tissue staining, biomarker detection, and functional assessment. The protective effect of aC5a-FNA against cerebral IRI in living animals may pave the way for the translation of FNA from bench to bedside and broaden the horizon of FNA in the field of biomedicine.

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.