No-reflow after stroke reperfusion therapy: An emerging phenomenon to be explored.

In the field of stroke thrombectomy, ineffective clinical and angiographic reperfusion after successful recanalization has drawn attention. Partial or complete microcirculatory reperfusion failure after the achievement of full patency of a former obstructed large vessel, known as the "no-reflow phenomenon" or "microvascular obstruction," was first reported in the 1960s and was later detected in both experimental models and patients with stroke. The no-reflow phenomenon (NRP) was reported to result from intraluminal occlusions formed by blood components and extraluminal constriction exerted by the surrounding structures of the vessel wall. More recently, an emerging number of clinical studies have estimated the prevalence of the NRP in stroke patients following reperfusion therapy, ranging from 3.3% to 63% depending on its evaluation methods or study population. Studies also demonstrated its detrimental effects on infarction progress and neurological outcomes. In this review, we discuss the research advances, underlying pathogenesis, diagnostic techniques, and management approaches concerning the no-reflow phenomenon in the stroke population to provide a comprehensive understanding of this phenomenon and offer references for future investigations.

Correction: An E-selectin targeting and MMP-2-responsive dextran-curcumin polymeric prodrug for targeted therapy of acute kidney injury.

Correction for 'An E-selectin targeting and MMP-2-responsive dextran-curcumin polymeric prodrug for targeted therapy of acute kidney injury' by Jing-Bo Hu et al., Biomater. Sci., 2018, 6, 3397-3409, https://doi.org/10.1039/C8BM00813B.

Positive Chemotaxis of CREKA-Modified Ceria@Polydopamine Biomimetic Nanoswimmers for Enhanced Penetration and Chemo-photothermal Tumor Therapy.

Tumor interstitial pressure represents the greatest barrier against drug diffusion into the depth of the tumor. Biometric nanomotors highlight the possibility of enhanced deep penetration and improve cellular uptake. However, control of their directionality remains difficult to achieve. Herein, we report cysteine-arginine-glutamic acid-lysine-alanine (CREKA)-modified ceria@polydopamine nanobowls as tumor microenvironment-fueled nanoscale motors for positive chemotaxis into the tumor depth or toward tumor cells. Upon laser irradiation, this nanoswimmer rapidly depletes the tumor microenvironment-specific hydrogen peroxide (H2O2) in the nanobowl, contributing to a self-generated gradient and subsequently propulsion (9.5 µm/s at 46 °C). Moreover, the asymmetrical modification of CREKA on nanobowls could automatically reconfigure the motion direction toward tumor depth or tumor cells in response to receptor-ligand interaction, leading to a deep penetration (70 µm in multicellular spheroids) and enhanced antitumor effects over conventional nanomedicine-induced chemo-photothermal therapy (tumor growth inhibition rate: 84.2% versus 56.9%). Thus, controlling the direction of nanomotors holds considerable potential for improved antitumor responses, especially in solid tumors with high tumor interstitial pressure.

A photo-activable nano-agonist for the two-signal model of T cell in vivo activation.

The two-signal model of T cell activation has helped shape our understanding of the adaptive immune response for over four decades. According to the model, activation of T cells requires a stimulus through the T cell receptor/CD3 complex (signal 1) and a costimulatory signal 2. Stimulation of activatory signals via T cell agonists has thus emerged. However, for a robust T cell activation, it necessitates not only the presence of both signal 1 and signal 2, but also a high signaling strength. Herein, we report a photo-activable nano-agonist for the two-signal model of T cell in vivo activation. A UV-crosslinkable polymer is coated onto upconversion nanoparticles with satisfactory NIR-to-UV light conversion efficiency. Then dual signal molecules, i.e., signal 1 and signal 2, are conjugated to the polymer end to yield the photo-activable T cell nano-agonist. In melanoma and breast cancer models, photo-activable nano-agonist could bind onto corresponding activatory receptors on the surface of T cells, but has limited activity without the application of NIR light (absence of photo-crosslinking of receptors and consequently a poor signaling strength). While when the NIR light is switched on locally, T cells in tumor are remarkably activated and kill tumor cells effectively. Moreover, we do not observe any detectable toxicities related to the photo-activable nano-agonist. We believe with two activatory signals being simultaneously strengthened by local photo-switched crosslinking, T cells realize a robust and selective activation in tumor and, consequently contribute to an enhanced and safe tumor immunotherapy.

Factors affecting the outcomes of tirofiban after endovascular treatment in acute ischemic stroke: Experience from a single center.

AIMS: To investigate the predicted factors influencing the outcomes in acute ischemic stroke (AIS) patients who received tirofiban after endovascular treatment (EVT) and the optimal administration of tirofiban. METHODS: In this retrospective study, AIS patients who received EVT followed by tirofiban between January 2017 and October 2021 were enrolled. The dose and duration of tirofiban were adjusted by trained clinicians according to the patient's clinical status. A reduction of at least four points on the National Institutes of Health Stroke Scale (NIHSS) after tirofiban compared with that before tirofiban was defined as an effective response. A modified ranking scale (mRS) of 0-2 was defined as a favorable outcome at a 90-day follow-up. RESULTS: A total of 260 consecutive patients were enrolled, and 36.5% of patients achieved a favorable outcome. The modified thrombolysis in cerebral infarction (mTICI) 2b-3 occurred in 93.5% of patients. Symptomatic intracerebral hemorrhage (sICH) occurred in 6.2% of patients, and the mortality at 90-day follow-up was 16.9%. Duration of tirofiban >24 h (adjusted OR: 2.545; 95% CI: 1.008-6.423; p = 0.048) and effective response to tirofiban (adjusted OR: 25.562; 95% CI: 9.794-66.715; p < 0.001) were related to the favorable outcome (mRS 0-2). Higher NIHSS (adjusted OR: 0.855; 95% CI: 0.809-0.904; p < 0.001) and glucose level on admission (adjusted OR: 0.843; 95% CI: 0.731-0.971; p = 0.018) were predictive for the unfavorable outcome (mRS 3-6). CONCLUSIONS: An effective response to tirofiban is an independent factor in predicting the long-term efficacy outcome, and extending the duration of tirofiban is beneficial for neurological improvement.

Recent Strategies to Address Hypoxic Tumor Environments in Photodynamic Therapy.

Photodynamic therapy (PDT) has become a promising method of cancer treatment due to its unique properties, such as noninvasiveness and low toxicity. The efficacy of PDT is, however, significantly reduced by the hypoxia tumor environments, because PDT involves the generation of reactive oxygen species (ROS), which requires the great consumption of oxygen. Moreover, the consumption of oxygen caused by PDT would further exacerbate the hypoxia condition, which leads to angiogenesis, invasion of tumors to other parts, and metastasis. Therefore, many research studies have been conducted to design nanoplatforms that can alleviate tumor hypoxia and enhance PDT. Herein, the recent progress on strategies for overcoming tumor hypoxia is reviewed, including the direct transport of oxygen to the tumor site by O2 carriers, the in situ generation of oxygen by decomposition of oxygen-containing compounds, reduced O2 consumption, as well as the regulation of tumor microenvironments. Limitations and future perspectives of these technologies to improve PDT are also discussed.

A Luminol-Based Self-Illuminating Nanocage as a Reactive Oxygen Species Amplifier to Enhance Deep Tumor Penetration and Synergistic Therapy.

The dense extracellular matrix (ECM) in tumor tissues resists drug diffusion into tumors and leads to a poor prognosis. To address this problem, glucose oxidase (GOx)-modified ferritin loaded with luminol-curcumin was fabricated. Once delivered to the tumor, this luminol-based self-illuminating nanocage could actively convert glucose to reactive oxygen species (ROS) to achieve starvation therapy. Then, excessive ROS were transmitted to luminol, thereby emitting 425 nm blue-violet light. Momentarily, light was further absorbed by curcumin and ROS production was amplified. Abundant ROS helps break down the ECM network to penetrate deep into tumors. In addition, ROS produced after cell internalization can induce apoptosis of tumor cells by decreasing the mitochondrial membrane potential and can promote ferroptosis by consuming reduced glutathione. Effective penetration and multiple pathways inducing tumor cell death contributed to the efficient antitumor effect (tumor inhibition rate of GOx-modified ferritin loaded with luminol-curcumin: 71.73%). This study developed a glucose-driven self-illuminating nanocage for active tumor penetration via ROS-mediated destruction of the ECM and provided the synergetic mechanism of apoptosis and ferroptosis.

Biomimetic Melanosomes Promote Orientation-Selective Delivery and Melanocyte Pigmentation in the H2O2-Induced Vitiligo Mouse Model.

Extremely limited drug retention and depigmentation represent the greatest barriers against vitiligo treatment advancement. Here, inspired by biological melanosomes, the primary melanin transporter, we developed biomimetic melanosomes to combat reactive oxygen species (ROS)-mediated melanocyte damage and depigmentation. Briefly, methylprednisolone (MPS) and melanin-mimicking polydopamine (PDA) were encapsulated inside lysine-proline-valine (KPV)-modified deformable liposomes (KPV-Lipos). Owing to their phospholipid bilayer flexibility and the specific affinity for melanocortin 1 receptor (MC1R), KPV-Lipos exhibited 1.43-fold greater skin deposition than traditional liposomes. The binding of KPV and its receptor also contributed to activating the cAMP-tyrosinase (TYR) signaling pathway, improving the endogenous melanin content. In addition, PDA mimicked melanosomes as it effectively increased the exogenous melanin content and scavenged ROS. Meanwhile, MPS inhibited inflammatory cytokine secretion, limiting the depigmented area. Ultimately, the biomimetic melanosomes affected the skin color of mice with H2O2-induced vitiligo. These melanosomes show potential as a universal platform for the self-supply of melanin by self-driven melanin synthesis with exogenous supplementation. Furthermore, this study offers ideas for the production of artificial packed melanosome substitutes for melanocyte-related diseases.

Recent advances in nanotherapeutics for the treatment and prevention of acute kidney injury.

Acute kidney injury (AKI) is a serious kidney disease without specific medications currently except for expensive dialysis treatment. Some potential drugs are limited due to their high hydrophobicity, poor in vivo stability, low bioavailability and possible adverse effects. Besides, kidney-targeted drugs are not common and small molecules are cleared too quickly to achieve effective drug concentrations in injured kidneys. These problems limit the development of pharmacological therapy for AKI. Nanotherapeutics based on nanotechnology have been proved to be an emerging and promising treatment strategy for AKI, which may solve the pharmacological therapy dilemma. More and more nanotherapeutics with different physicochemical properties are developed to efficiently deliver drugs, increase accumulation and control release of drugs in injury kidneys and also directly as effective antioxidants. Here, we discuss the recent nanotherapeutics applied in the treatment and prevention of AKI with improved effectiveness and few side effects.

Synergistic effect of tumor chemo-immunotherapy induced by leukocyte-hitchhiking thermal-sensitive micelles.

Some specific chemotherapeutic drugs are able to enhance tumor immunogenicity and facilitate antitumor immunity by inducing immunogenic cell death (ICD). However, tumor immunosuppression induced by the adenosine pathway hampers this effect. In this study, E-selectin-modified thermal-sensitive micelles are designed to co-deliver a chemotherapeutic drug (doxorubicin, DOX) and an A2A adenosine receptor antagonist (SCH 58261), which simultaneously exhibit chemo-immunotherapeutic effects when applied with microwave irradiation. After intravenous injection, the fabricated micelles effectively adhere to the surface of leukocytes in peripheral blood mediated by E-selectin, and thereby hitchhiking with leukocytes to achieve a higher accumulation at the tumor site. Further, local microwave irradiation is applied to induce hyperthermia and accelerates the release rate of drugs from micelles. Rapidly released DOX induces tumor ICD and elicits tumor-specific immunity, while SCH 58261 alleviates immunosuppression caused by the adenosine pathway, further enhancing DOX-induced antitumor immunity. In conclusion, this study presents a strategy to increase the tumor accumulation of drugs by hitchhiking with leukocytes, and the synergistic strategy of chemo-immunotherapy not only effectively arrested primary tumor growth, but also exhibited superior effects in terms of antimetastasis, antirecurrence and antirechallenge.

Renal Cell-Targeted Drug Delivery Strategy for Acute Kidney Injury and Chronic Kidney Disease: A Mini-Review.

Kidney diseases, including acute kidney injury (AKI) and chronic kidney disease (CKD), have become a global public health concern associated with high morbidity, mortality, and healthcare costs. However, at present, very few effective and specific drug therapies are available, owing to the poor therapeutic efficacy and systemic side effects. Kidney-targeted drug delivery, as a potential strategy for solving these problems, has received great attention in the fields of AKI and CKD in recent years. Here, we review the literature on renal targeted, more specifically, renal cell-targeted formulations of AKI and CKD that offered biodistribution data. First, we provide a broad overview of the unique structural characteristics and injured cells of acute and chronic injured kidneys. We then separately summarize literature examples of renal targeted formulations according to the difference of target cells and elaborate on the appropriate formulation design criteria for AKI and CKD. Finally, we propose a hypothetic strategy to improve the renal accumulation of glomerular cell-targeted formulation by escaping the uptake of the reticuloendothelial system and provide some perspectives for future studies.

Nanomaterials-Based Photodynamic Therapy with Combined Treatment Improves Antitumor Efficacy Through Boosting Immunogenic Cell Death.

Benefiting from the rapid development of nanotechnology, photodynamic therapy (PDT) is arising as a novel non-invasive clinical treatment for specific cancers, which exerts direct efficacy in destroying primary tumors by generating excessive cytotoxic reactive oxygen species (ROS). Notably, PDT-induced cell death is related to T cell-mediated antitumor immune responses through induction of immunogenic cell death (ICD). However, ICD elicited via PDT is not strong enough and is limited by immunosuppressive tumor microenvironment (ITM). Therefore, it is necessary to improve PDT efficacy through enhancing ICD with the combination of synergistic tumor therapies. Herein, the recent progress of nanomaterials-based PDT combined with chemotherapy, photothermal therapy, radiotherapy, and immunotherapy, employing ICD-boosted treatments is reviewed. An outlook about the future application in clinics of nanomaterials-based PDT strategies is also mentioned.

Cancer-cell-biomimetic Upconversion nanoparticles combining chemo-photodynamic therapy and CD73 blockade for metastatic triple-negative breast cancer.

Photodynamic therapy (PDT) and chemotherapy show clinical promise in destroying orthotopic tumors but are insufficient against abscopal metastases. The research reports the combined application of an anti-CD73 antibody and chemo-PDT to synergistically amplify the anti-metastatic effects of T cell-mediated antitumor immunity. The cancer cell membrane (CM)-cloaked upconversion nanoparticles, integrating rose bengal (RB) and the reactive oxygen species (ROS)-sensitive polymer polyethylene glycol-thioketal-doxorubicin (PEG-TK-DOX, i.e., PTD), are tailored for near-infrared (NIR)-triggered chemo-PDT. CM camouflage enables nanoparticles' excellent tumor-targeting abilities and immune escape from macrophages. The combination of PDT and chemotherapy presents strong synergistic antitumor efficacy and synchronously causes a series of immunogenic cell death (ICD), leading to tumor-specific immunity. The anti-CD73 antibody prevents the immunosuppression phenomenon in tumors by blocking the adenosine pathway, and it is emerging as a sufficient immune checkpoint blockade when combined with ICD-elicited tumor therapies. As cancer membrane camouflaged nanoparticles CM@UCNP-RB/PTD combined with anti-CD73 antibodies, synergistic efficacy of chemotherapy and PDT not only destroys the orthotopic tumors by DOX and cytotoxic ROS but also prevents abscopal tumor metastasis via inducing systemic cytotoxic T cell responses with CD73 blockade. This strategy is promising in curing metastatic triple-negative breast cancer in preclinical research.

Combination Cancer Immunotherapy of Nanoparticle-Based Immunogenic Cell Death Inducers and Immune Checkpoint Inhibitors.

Cancer immunotherapy is a promising treatment strategy that aims to strengthen immune responses against cancer. However, the low immunogenicity of tumor cells and inhibition of effector T cells in the tumor immunosuppressive microenvironment remain two major challenges. Immunogenic cell death (ICD) inducers not only directly kill cancer cells but also increase the tumor immunogenicity and induce antitumor immune responses. Immune checkpoint inhibitors can alleviate the inhibition of immune cells. Significantly, the combination of ICD inducers and immune checkpoint inhibitors elicits a remarkable antitumor effect. Nanoparticles confer the ability to modulate systemic biodistribution and achieve targeted accumulation of administered therapeutic agents, thereby facilitating the clinical translation of immunotherapies based on ICD inducers in a safe and effective manner. In this review, we summarize the nanoparticle-based chemical and physical cues that induce effective tumor ICD and elicit an antitumor immune response. In particular, combination of ICD inducers with immune checkpoint inhibitors can further reverse immunosuppression and prevent tumor metastasis and recurrence. An overview of the future challenges and prospects is also provided.

ROS-responsive chitosan-SS31 prodrug for AKI therapy via rapid distribution in the kidney and long-term retention in the renal tubule.

The development of drugs with rapid distribution in the kidney and long-term retention in the renal tubule is a breakthrough for enhanced treatment of acute kidney injury (AKI). Here, l-serine-modified chitosan (SC) was synthesized as a potential AKI kidney-targeting agent due to the native cationic property of chitosan and specific interaction between kidney injury molecule-1 (Kim-1) and serine. Results indicated that SC was rapidly accumulated and long-term retained in ischemia-reperfusion-induced AKI kidneys, especially in renal tubules, which was possibly due to the specific interactions between SC and Kim-1. SC-TK-SS31 was then prepared by conjugating SS31, a mitochondria-targeted antioxidant, to SC via reactive oxygen species (ROS)-sensitive thioketal linker. Because of the effective renal distribution combined with ROS-responsive drug release behavior, the administration of SC-TK-SS31 led to an enhanced therapeutic effect of SS31 by protecting mitochondria from damage and reducing the oxidative stress, inflammation, and cell apoptosis.

NIR-Triggered Sequentially Responsive Nanocarriers Amplified Cascade Synergistic Effect of Chemo-Photodynamic Therapy with Inspired Antitumor Immunity.

A desirable cancer therapeutic strategy is supposed to have effective ability to not only exert maximum anticancer ability but also inspire antitumor immunity for preventing tumor relapse and metastasis. During this research, multifunctional upconversion nanoparticles (UCNPs) coated by ROS-responsive micelles are prepared for tumor targeting and near-infrared (NIR)-triggered photodynamic therapy (PDT)-combined synergistic effect of chemotherapy. Moreover, both PDT and chemotherapy agents could activate antitumor immunity via inducing immunogenic cell death with CD8+ and CD4+ T cells infiltrating in tumors. Through the experiments, intravenous administration of multifunctional nanocarriers with noninvasive NIR irradiation destroys the orthotopic tumors and efficiently suppresses lung metastasis in a metastatic triple-negative breast cancer model by cascade-amplifying chemo-PDT and systemic antitumor immunity. In conclusion, this study provides prospective chemo-PDT with inspired antitumor immunity for metastatic cancer treatment.

Sialic acid-modified chitosan oligosaccharide-based biphasic calcium phosphate promote synergetic bone formation in rheumatoid arthritis therapy.

Therapeutic goals for rheumatoid arthritis (RA) consist of inhibiting the inflammatory response and repairing the damaged bone/cartilage. Tissue engineering could achieve both goals, however, it was hindered due to the lack of biologically relevant tissue complexity, limitation in covering the entire polyarthritis lesions and requirement of extra surgical implantation. Integrating nanotechnologies into clinically sized implants represents a major opportunity to overcome these problems. Herein, we designed a sialic acid (SA)-modified chitosan oligosaccharide-based biphasic calcium phosphate (BCP), a biomimetic nanoplatform that could load with methotrexate. We found that SA modification could not only improve the accumulation of the designed organic-inorganic nanoplatform in arthritic paws (34.38% higher than those without SA modification at 48 h), but also cooperate with BCP to exert synergetic mineralization of calcium phosphate, allowing more osteoblasts to attach, proliferate and differentiate. The more differentiated osteoblasts produced 4.46-fold type I collagen and 2.60-fold osteoprotegerin compared to the control group. Besides, the disassembled nanorods released chitosan oligosaccharide-based micelles, revealing a cartilage-protective effect by reducing the loss of glycosaminoglycan. All these improvements contributed to the light inflammatory response and reduced destruction on cartilage/bone. The findings provide a novel strategy for RA therapy via nanometer-scale dimension mimicking the natural tissues.

ROS-responsive nano-drug delivery system combining mitochondria-targeting ceria nanoparticles with atorvastatin for acute kidney injury.

Acute kidney injury (AKI) caused by sepsis is a serious disease which mitochondrial oxidative stress and inflammatory play a key role in its pathophysiology. Ceria nanoparticles hold strong and recyclable reactive oxygen species (ROS)-scavenging activity, have been applied to treat ROS-related diseases. However, ceria nanoparticles can't selectively target mitochondria and the ultra-small ceria nanoparticles are easily agglomerated. To overcome these shortcomings and improve therapeutic efficiency, we designed an ROS-responsive nano-drug delivery system combining mitochondria-targeting ceria nanoparticles with atorvastatin for acute kidney injury. Methods: Ceria nanoparticles were modified with triphenylphosphine (TCeria NPs), followed by coating with ROS-responsive organic polymer (mPEG-TK-PLGA) and loaded atorvastatin (Atv/PTP-TCeria NPs). The physicochemical properties, in vitro drug release profiles, mitochondria-targeting ability, in vitro antioxidant, anti-apoptotic activity and in vivo treatment efficacy of Atv/PTP-TCeria NPs were examined. Results: Atv/PTP-TCeria NPs could accumulate in kidneys and hold a great ability to ROS-responsively release drug and TCeria NPs could target mitochondria to eliminate excessive ROS. In vitro study suggested Atv/PTP-TCeria NPs exhibited superior antioxidant and anti-apoptotic activity. In vivo study showed that Atv/PTP-TCeria NPs effectively decreased oxidative stress and inflammatory, could protect the mitochondrial structure, reduced apoptosis of tubular cell and tubular necrosis in the sepsis-induced AKI mice model. Conclusions: This ROS-responsive nano-drug delivery system combining mitochondria-targeting ceria nanoparticles with atorvastatin has favorable potentials in the sepsis-induced AKI therapy.

Cyto-friendly polymerization at cell surfaces modulates cell fate by clustering cell-surface receptors.

Lots of strategies, e.g. using multivalent synthetic polymers, have been developed to control the spatial distribution of cell-surface receptors, thus modulating the cell function and fate in a custom-tailored manner. However, clustering cell-surface receptors via multivalent synthetic polymers is highly dependent on the structure as well as the ligand-density of the polymers, which may impose difficulties on the synthesis of polymers with a high density of ligands. Here, we pioneered the utilization of a cyto-friendly polymerization at the cell surface to cluster cell-surface receptors. As a proof of concept, an anti-CD20 aptamer conjugated macromer was initially synthesized, which was then efficiently and stably introduced onto the Raji cell surface via ligand-receptor interaction. With the assistance of an initiator, i.e. ammonium peroxysulfate (APS), the macromer bound onto the Raji cell surface polymerized, inducing the clustering of CD20 receptors, and thereby triggering cell apoptosis. This cell-surface polymerization induced cell-surface receptor crosslinking could alternatively be applied in modulating the fates and functions of other cells, especially those mediated by the spatial distribution of cell-surface receptors, such as T cell activation. Our work opens new possibilities in the area of chemical biology to some extent.