Codelivery of Anti‐PD‐1 Antibody and Paclitaxel with Matrix Metalloproteinase and pH Dual‐Sensitive Micelles for Enhanced Tumor Chemoimmunotherapy

Immune checkpoint blockade (ICB) is demonstrating great potential in cancer immunotherapy nowadays. Yet, the low response rate to ICB remains an urgent challenge for tumor immunotherapy. A pH and matrix metalloproteinase dual‐sensitive micellar nanocarrier showing spatio‐temporally controlled release of anti‐PD‐1 antibody (aPD‐1) and paclitaxel (PTX) in solid tumors is prepared to realize synergistic cancer chemoimmunotherapy. Antitumor immunity can be activated by PTX‐induced immunogenic cell death (ICD), while aPD‐1 blocks the PD‐1/PD‐L1 axis to suppress the immune escape due to PTX‐induced PD‐L1 up‐regulation, thus resulting in a synergistic antitumor chemoimmunotherapy. Through decoration with a sheddable polyethylene glycol (PEG) shell, the nanodrug may better accumulate in tumors to boost the synergistic antitumor treatment in a mouse melanoma model. The present study demonstrates a potent antitumor chemoimmunotherapy utilizing tumor microenvironment‐sensitive micelles bearing a sheddable PEG layer to mediate site‐specific sequential release of aPD‐1 and PTX.     

Engineering Novel Targeted Boron‐10‐Enriched Theranostic Nanomedicine to Combat against Murine Brain Tumors via MR Imaging‐Guided Boron Neutron Capture Therapy

Glioblastoma multiforme (GBM) is a very common type of “incurable” malignant brain tumor. Although many treatment options are currently available, most of them eventually fail due to its recurrence. Boron neutron capture therapy (BNCT) emerges as an alternative noninvasive therapeutic treatment modality. The major challenge in treating GBMs using BNCT is to achieve selective imaging, targeting, and sufficient accumulation of boron‐containing drug at the tumor site so that effective destruction of tumor cells can be achieved without harming the normal brain cells. To tackle this challenge, this study demonstrates for the first time that an unprecedented ¹⁰B‐enriched (96% ¹⁰B enrichment) boron nanoparticle nanomedicine (¹⁰BSGRF NPs) surface‐modified with a Fluorescein isothiocyanate (FITC)‐labeled RGD‐K peptide can pass through the brain blood barrier, selectively target at GBM brain tumor sites, and deliver high therapeutic dosage (50.5 µg ¹⁰B g^?1 cells) of boron atoms to tumor cells with a good tumor‐to‐blood boron ratio of 2.8. The ¹⁰BSGRF NPs not only can enhance the contrast of magnetic resonance (MR) imaging to help diagnose the location/size/progress of brain tumor, but also effectively suppress murine brain tumors via MR imaging‐guided BNCT, prolonging the half‐life of mice from 22 d (untreated group) to 39 d.     

Quantitative Analysis of Multiple Proteins of Different Invasive Tumor Cell Lines at the Same Single‐Cell Level

Tumor cell invasion is pivotal to the development, metastasis, and prognosis of tumors. It is reported that the invasive ability of tumor cells is mainly dependent on the expression levels of membrane type‐1 matrix metalloproteinase (MT1‐MMP) and integrin α_Vβ₃ proteins on cell membranes. To precisely distinguish between tumor cells with different invasive abilities, it is important to establish a highly sensitive and precise quantification method to differentiate the expression levels of MT1‐MMP and integrin α_Vβ₃ in the same single tumor cell at the same time. Herein, two functional peptides to construct red‐emissive Au₂₆ clusters and green‐emissive Ag₁₂ clusters are reported. Moreover, the Au₂₆ clusters and Ag₁₂ clusters have the ability to specifically target MT1‐MMP and integrin α_Vβ₃, respectively, in the same single cell at the same time. By utilizing the fluorescent properties and metallic compositions of metal clusters, the MT1‐MMP and integrin α_Vβ₃ levels of the more invasive SiHa cells or the less invasive HeLa cells are simultaneously and quantitatively differentiated via laser ablation inductively coupled plasma mass spectrometry. This method of quantitatively detecting multiple invasive proteins on the same cell is of great value for accurately diagnosing aggressive tumors and monitoring the invasiveness of these tumors.     

Cu2MoS4/Au Heterostructures with Enhanced Catalase‐Like Activity and Photoconversion Efficiency for Primary/Metastatic Tumors Eradication by Phototherapy‐Induced Immunotherapy

Photoimmunotherapy can not only effectively ablate the primary tumor but also trigger strong antitumor immune responses against metastatic tumors by inducing immunogenic cell death. Herein, Cu₂MoS₄ (CMS)/Au heterostructures are constructed by depositing plasmonic Au nanoparticles onto CMS nanosheets, which exhibit enhanced absorption in near‐infrared (NIR) region due to the newly formed mid‐gap state across the Fermi level based on the hybridization between Au 5d orbitals and S 3p orbitals, thus resulting in more excellent photothermal therapy and photodynamic therapy (PDT) effect than single CMS upon NIR laser irradiation. The CMS and CMS/Au can also serve as catalase to effectively relieve tumor hypoxia, which can enhance the therapeutic effect of O₂‐dependent PDT. Notably, the NIR laser‐irradiated CMS/Au can elicit strong immune responses via promoting dendritic cells maturation, cytokine secretion, and activating antitumor effector T‐cell responses for both primary and metastatic tumors eradication. Moreover, CMS/Au exhibits outstanding photoacoustic and computed tomography imaging performance owing to its excellent photothermal conversion and X‐ray attenuation ability. Overall, the work provides an imaging‐guided and phototherapy‐induced immunotherapy based on constructing CMS/Au heterostructures for effectively tumor ablation and cancer metastasis inhibition.     

TGF‐β1 Conjugated to Gold Nanoparticles Results in Protein Conformational Changes and Attenuates the Biological Function

Gold nanoparticles (AuNPs) are widely used as carriers or therapeutic agents due to their great biocompatibility and unique physical properties. Transforming growth factor‐beta 1 (TGF‐β1), a member of the cysteine‐knot structural superfamily, plays a pivotal role in many diseases and is known as an immunosuppressive agent that attenuates immune response resulting in tumor growth. The results reported herein reflect strong interactions between TGF‐β1 and the surface of AuNPs when incubated with serum‐containing medium, and demonstrate a time‐ and dose‐dependent pattern. Compared with other serum proteins that can also bind to the AuNP surface, AuNP–TGFβ1 conjugate is a thermodynamically favored compound. Epithelial cells undergo epithelial–mesenchymal transition (EMT) upon treatment with TGF‐β1; however, treatment with AuNPs reverses this effect, as detected by cell morphology and expression levels of EMT markers. TGF‐β1 is found to bind to AuNPs through S–Au bonds by X‐ray photoelectron spectroscopy. Fourier transform infrared spectroscopy is employed to analyze the conformational changes of TGF‐β1 on the surface of AuNPs. The results indicate that TGF‐β1 undergoes significant conformational changes at both secondary and tertiary structural levels after conjugation to the AuNP surface, which results in the deactivation of TGF‐β1 protein. An in vivo experiment also shows that addition of AuNPs attenuates the growth of TGF‐β1‐secreting murine bladder tumor 2 cells in syngeneic C3H/HeN mice, but not in immunocompromised NOD‐SCID mice, and this is associated with an increase in the number of tumor‐infiltrating CD4⁺ and CD8⁺ T lymphocytes and a decrease in the number of intrasplenic Foxp3(+) lymphocytes. The findings demonstrate that AuNPs may be a promising agent for modulating tumor immunity through inhibiting immunosuppressive TGF‐β1 signaling.     

An Activatable Nano‐Prodrug for Treating Tyrosine‐Kinase‐Inhibitor‐Resistant Non‐Small Cell Lung Cancer and for Optoacoustic and Fluorescent Imaging

Non‐small cell lung cancer (NSCLC) is the most common type of lung cancer and the cause of high rate of mortality. The epidermal growth factor receptor (EGFR)‐targeted tyrosine kinase inhibitors are used to treat NSCLC, yet their curative effects are usually compromised by drug resistance. This study demonstrates a nanodrug for treating tyrosine‐kinase‐inhibitor‐resistant NSCLC through inhibiting upstream and downstream EGFR signaling pathways. The main molecule of the nanodrug is synthesized by linking a tyrosine kinase inhibitor gefitinib and a near‐infrared dye (NIR) on each side of a disulfide via carbonate bonds, and the nanodrug is then obtained through nanoparticle formation of the main molecule in aqueous medium and concomitant encapsulation of a serine threonine protein kinase (Akt) inhibitor celastrol. Upon administration, the nanodrug accumulates at the tumor region of NSCLC‐bearing mice and releases the drugs for tumor inhibition, and the dye for fluorescence and optoacoustic imaging. Through suppressing the phosphorylation of upstream EGFR and downstream Akt in the EGFR pathway by gefitinib and celastrol, respectively, the nanodrug exhibits high inhibition efficacy against orthotopic NSCLC in mouse models.     

Combretastatin A4 Nanodrug‐Induced MMP9 Amplification Boosts Tumor‐Selective Release of Doxorubicin Prodrug

Tumor‐associated enzyme‐activated prodrugs can potentially improve the selectivity of chemotherapeutics. However, the paucity of tumor‐associated enzymes which are essential for prodrug activation usually limits the antitumor potency. A cooperative strategy that utilizes combretastatin A4 nanodrug (CA4‐NPs) and matrix metalloproteinase 9 (MMP9)‐activated doxorubicin prodrug (MMP9‐DOX‐NPs) is developed. CA4 is a typical vascular disrupting agent that can selectively disrupt immature tumor blood vessels and exacerbate the tumor hypoxia state. After treatment with CA4‐NPs, MMP9 expression can be significantly enhanced by 5.6‐fold in treated tumors, which further boosts tumor‐selective active drug release of MMP9‐DOX‐NPs by 3.7‐fold in an orthotopic 4T1 mammary adenocarcinoma mouse model. The sequential delivery of CA4‐NPs and MMP9‐DOX‐NPs exhibits enhanced antitumor efficacy with reduced systemic toxicity compared with the noncooperative controls.     

Polyhydroxylated Metallofullerenols Stimulate IL‐1β Secretion of Macrophage through TLRs/MyD88/NF‐κB Pathway and NLRP3 Inflammasome Activation

Polyhydroxylated fullerenols especially gadolinium endohedral metallofullerenols (Gd@C₈₂(OH)₂₂) are shown as a promising agent for antitumor chemotherapeutics and good immunoregulatory effects with low toxicity. However, their underlying mechanism remains largely unclear. We found for the first time the persistent uptake and subcellular distribution of metallofullerenols in macrophages by taking advantages of synchrotron‐based scanning transmission X‐ray microscopy (STXM) with high spatial resolution of 30 nm. Gd@C₈₂(OH)₂₂ can significantly activate primary mouse macrophages to produce pro‐inflammatory cytokines like IL‐1β. Small interfering RNA (siRNA) knockdown shows that NLRP3 in?ammasomes, but not NLRC4, participate in fullerenol‐induced IL‐1β production. Potassium efflux, activation of P2X₇ receptor and intracellular reactive oxygen speciesare also important factors required for fullerenols‐induced IL‐1β release. Stronger NF‐κB signal triggered by Gd@C₈₂(OH)₂₂ is in agreement with higher pro‐IL‐1β expression than C₆₀(OH)₂₂. Interestingly, TLR4/MyD88 pathway but not TLR2 mediates IL‐1β secretion in Gd@C₈₂(OH)₂₂ exposure confirmed by macrophages from MyD88^?/?/TLR4^?/?/TLR2^?/? knockout mice, which is different from C₆₀(OH)₂₂. Our work demonstrated that fullerenols can greatly activate macrophage and promote IL‐1β production via both TLRs/MyD88/NF‐κB pathway and NLRP3 inflammasome activation, while Gd@C₈₂(OH)₂₂ had stronger ability C₆₀(OH)₂₂ due to the different electron affinity on the surface of carbon cage induced by the encaged gadolinium ion.     

Gold Nanoparticles Downregulate Interleukin‐1β‐Induced Pro‐Inflammatory Responses

Interleukin 1 beta (IL‐1β)‐dependent inflammatory disorders, such as rheumatoid arthritis and psoriasis, pose a serious medical burden worldwide, where patients face a lifetime of illness and treatment. Organogold compounds have been used since the 1930s to treat rheumatic and other IL‐1β‐dependent diseases and, though their mechanisms of action are still unclear, there is evidence that gold interferes with the transmission of inflammatory signalling. Here we show for the first time that citrate‐stabilized gold nanoparticles, in a size dependent manner, specifically downregulate cellular responses induced by IL‐1β both in vitro and in vivo. Our results indicate that the anti‐inflammatory activity of gold nanoparticles is associated with an extracellular interaction with IL‐1β, thus opening potentially novel options for further therapeutic applications.     

Long‐term effects of angiotensin II blockade with irbesartan on inflammatory markers in hemodialysis patients: A randomized double blind placebo controlled trial (SAFIR study)

Introduction: Low‐grade chronic inflammation is common in hemodialysis (HD) patients. Previous studies suggest an anti‐inflammatory effect of angiotensin II receptor blocker (ARB) treatment. The aim of this study was to compare the effect of ARB vs. placebo on plasma concentrations of inflammatory markers in HD patients. Methods: Adult HD patients were randomized for double‐blind treatment with the ARB irbesartan 150–300 mg/day or placebo. At baseline, 1 week, 3, 6, 9, and 12 months plasma high sensitivity C‐reactive protein (hsCRP), interleukin (IL)?1β, IL‐6, IL‐8, IL‐18, and transforming growth factor‐β (TGF‐β) were measured using Luminex and enzyme‐linked immunosorbent assay (ELISA) technology. Findings: Eighty‐two patients were randomized (placebo/ARB: 41/41). The groups did not differ in initial levels of any of the inflammatory markers (placebo/ARB median(range)): hsCRP 3.3(0.2–23.4)/2.7(0.2–29.6) μg/mL; IL‐1β 1.1(0.0–45.9)/1.1(0.0‐7.2) pg/mL; IL‐6 10(1–90)/12(1–84) pg/mL; IL‐8 31(9–134)/34(5–192) pg/mL; IL‐18 364(188–1343)/377(213–832) pg/mL; TGF‐β 3.2(0.8–13.9)/3.6(1.3–3.8) ng/mL. Overall, there was no significant difference in hsCRP, IL‐6, IL‐8, and TGF‐β between placebo and ARB‐treated patients during the study period, and hsCRP, IL‐6, IL‐8, and TGF‐β were relatively stable during the study period (P ≥ 0.18 in all tests for parallel curves, equal levels, and constant levels). The IL‐1β level was slightly different in the two groups over time, but not significantly (P = 0.09 in test for parallel curves) and it was also relatively stable during the study period (P ≥ 0.49 in tests for equal levels and constant level). IL‐18 was the only inflammatory marker which was not constant during the study period (P = 0.001 in test for constant level), but there was no significant difference between placebo and ARB‐treated (P ≥ 0.51 in tests for parallel curves and equal levels). Discussion: Inflammatory biomarkers were neither acutely, nor in the long‐term significantly affected by the ARB irbesartan. Our findings suggest that ARB treatment in HD patients does not offer protective anti‐inflammatory effects.     

Simulated Sunlight‐Mediated Photodynamic Therapy for Melanoma Skin Cancer by Titanium‐Dioxide‐Nanoparticle–Gold‐Nanocluster–Graphene Heterogeneous Nanocomposites

Simulated sunlight has promise as a light source able to alleviate the severe pain associated with patients during photodynamic therapy (PDT); however, low sunlight utilization efficiency of traditional photosensitizers dramatically limits its application. Titanium‐dioxide‐nanoparticle–gold‐nanocluster–graphene (TAG) heterogeneous nanocomposites are designed to efficiently utilize simulated sunlight for melanoma skin cancer PDT. The narrow band gap in gold nanoclusters (Au NCs), and staggered energy bands between Au NCs, titanium dioxide nanoparticles (TiO₂ NPs), and graphene can result in efficient utilization of simulated sunlight and separation of electron–hole pairs, facilitating the production of abundant hydroxyl and superoxide radicals. Under irradiation of simulated sunlight, TAG nanocomposites can trigger a series of toxicological responses in mouse B16F1 melanoma cells, such as intracellular reactive oxygen species production, glutathione depletion, heme oxygenase‐1 expression, and mitochondrial dysfunctions, resulting in severe cell death. Furthermore, intravenous or intratumoral administration of biocompatible TAG nanocomposites in B16F1‐tumor‐xenograft‐bearing mice can significantly inhibit tumor growth and cause severe pathological tumor tissue changes. All of these results demonstrate prominent simulated sunlight‐mediated PDT effects.     

Surface‐Engineering of Red Blood Cells as Artificial Antigen Presenting Cells Promising for Cancer Immunotherapy

The development of artificial antigen presenting cells (aAPCs) to mimic the functions of APCs such as dendritic cells (DCs) to stimulate T cells and induce antitumor immune responses has attracted substantial interests in cancer immunotherapy. In this work, a unique red blood cell (RBC)‐based aAPC system is designed by engineering antigen peptide‐loaded major histocompatibility complex‐I and CD28 activation antibody on RBC surface, which are further tethered with interleukin‐2 (IL2) as a proliferation and differentiation signal. Such RBC‐based aAPC‐IL2 (R‐aAPC‐IL2) can not only provide a flexible cell surface with appropriate biophysical parameters, but also mimic the cytokine paracrine delivery. Similar to the functions of matured DCs, the R‐aAPC‐IL2 cells can facilitate the proliferation of antigen‐specific CD8+ T cells and increase the secretion of inflammatory cytokines. As a proof‐of‐concept, we treated splenocytes from C57 mice with R‐aAPC‐IL2 and discovered those splenocytes induced significant cancer‐cell‐specific lysis, implying that the R‐aAPC‐IL2 were able to re‐educate T cells and induce adoptive immune response. This work thus presents a novel RBC‐based aAPC system which can mimic the functions of antigen presenting DCs to activate T cells, promising for applications in adoptive T cell transfer or even in direct activation of circulating T cells for cancer immunotherapy.     

Dual‐Functional Alginic Acid Hybrid Nanospheres for Cell Imaging and Drug Delivery

An effective and facile approach to prepare gold‐nanoparticle‐encapsulated alginic acid‐poly[2‐(diethylamino)ethyl methacrylate] monodisperse hybrid nanospheres (ALG–PDEA–Au) is developed by using monodisperse ALG–PDEA nanospheres as a precursor nanoparticulate reaction system. This approach utilizes particle‐interior chemistry, which avoids additional reductant or laborious separation process and, moreover, elegantly ensures that all the gold nanoparticles are located inside the hybrid nanospheres and every nanosphere is loaded with gold nanoparticles. These obtained ALG–PDEA–Au hybrid nanospheres have not only uniform size, similar surface properties, and good biocompatibility but also unique optical properties provided by the embedded gold nanoparticles. It is demonstrated that negatively charged ALG–PDEA–Au hybrid nanospheres can be internalized by human colorectal LoVo cancer cells and hence act as novel optical‐contrast reagents in tumor‐cell imaging by optical microscopy. Moreover, these hybrid nanospheres can also serve as biocompatible carriers for the loading and delivery of an anti‐cancer drug doxorubicin. In vitro cell viability tests reveal that drug‐loaded ALG–PDEA–Au hybrid nanospheres exhibit similar tumor cell inhibition to the free drug doxorubicin. Therefore, the obtained hybrid nanospheres successfully combine two functions, that is, cell imaging and drug delivery, into one single system, and may be of great application potential in other biomedical‐related areas.     

The neuroprotective effect of a traditional herbal (kyung‐ok‐ko) on transient middle cerebral artery occlusion‐Induced ischemic rat brain

Kyung‐ok‐ko (KOK) has been used for the treatment of central nervous system disorders such as amnesia, dementia, and cerebral ischemia. However, the effects of KOK on transient ischemic‐induced neuronal damage are still unclear. We examined whether KOK improves functional recovery and has a neuroprotective effect on infarction volume after transient middle cerebral artery occlusion (MCAO). KOK (50, 100, and 200 mg/kg) was administered orally following reperfusion and twice per day for 14 days post‐MCAO. Infarction volume was measured using 2% 2‐3‐5 triphenylterazolium (TTC) staining at 14 days post‐MCAO and alteration in regional cerebral blood flow (rCBF) after KOK treatment was monitored. Functional improvement was evaluated using adhesive removal and treadmill tests at 1, 7, and 14 days post‐MCAO. Also, apoptotic cell death was assessed by terminal deoxynucleotidyl‐transferase mediated d‐UTP‐biotin nick end (TUNEL) in the peri‐infarction region. The protein level of inflammatory cytokines such as tumor necrosis factor‐α (TNF‐α), interleukin‐1α (IL‐1α), and interleukin‐1β (IL‐1β) was measured in the ischemic core, ischemic border zone, and contralateral hemisphere regions. The KOK‐treated group showed both reduced infarction volume and behavior tests demonstrated a significant improvement as compared to the control. Also, in the KOK‐treated group, rCBF was recovered to near normal levels. The apoptotic cells were significantly decreased as compared with the control group in the ischemic peri‐infarction area. Furthermore, the level of TNF‐α, IL‐1β, and IL‐1α was decreased. These results suggest that KOK may improve functional outcome by inhibiting inflammatory cytokines (TNF‐α, IL‐1β, and IL‐1α) in neuronal injury such as ischemic stroke.     

A Chiral‐Nanoassemblies‐Enabled Strategy for Simultaneously Profiling Surface Glycoprotein and MicroRNA in Living Cells

Assemblies of nanomaterials for biological applications in living cells have attracted much attention. Herein, graphene oxide (GO)–gold nanoparticle (Au NP) assemblies are driven by a splint DNA strand, which is designed with two regions at both ends that are complementary with the DNA sequence anchored on the surface of the GO and the Au NPs. In the presence of microRNA (miR)‐21 and epithelial cell‐adhesion molecule (EpCAM), the hybridization of miR‐21 with a molecular probe leads to the separation of 6‐fluorescein‐phosphoramidite‐modified Au NPs from GO, resulting in a decrease in the Raman signal, while EpCAM recognition reduces circular dichroism (CD) signals. The CD signals reverse from negative in original assemblies into positive when reacted with cells, which correlates with two enantiomer geometries. The EpCAM detection has a good linear range of 8.47–74.78 pg mL^?1 and a limit of detection (LOD) of 3.63 pg mL^?1, whereas miR‐21 detection displays an outstanding linear range of 0.07–13.68 amol ng^?1_RNA and LOD of 0.03 amol ng^?1_RNA. All the results are in good agreement with those of the Raman and confocal bioimaging. The strategy opens up an avenue to allow the highly accurate and reliable diagnosis (dual targets) of clinic diseases.     

Sensitive Detection of Carcinoembryonic Antigen Using Stability‐Limited Few‐Layer Black Phosphorus as an Electron Donor and a Reservoir

The instability of few‐layer black phosphorus (FL‐BP) hampers its further applications. Here, it can be demonstrated that the instability of FL‐BP can also be the advantage for application in biosensor. First, gold nanoparticle/FL‐BP (BP‐Au) hybrid is facilely synthesized by mixing Au precursor with FL‐BP. BP‐Au shows outstanding catalytic activity (K = 1120 s^?1 g^?1) and low activation energy (17.53 kJ mol^?1) for reducing 4‐nitrophenol, which is attributed to the electron‐reservoir and electron‐donor properties of FL‐BP, and synergistic interaction of Au nanoparticles and FL‐BP. Oxidation of FL‐BP after catalytic reaction is further confirmed by transmission electron microscope, X‐ray photoelectron spectroscopy, and zeta potentials. Second, the catalytic activity of BP‐Au can be reversibly switched from “inactive” to “active” upon treatment with antibody and antigen in solution, thus providing a versatile platform for label‐free colorimetric detection of biomarkers. The sensor shows a wide detection range (1 pg mL^?1 to –10 µg mL^?1), high sensitivity (0.20 pg mL^?1), and selectivity for detecting carcinoembryonic antigen (CEA). Finally, the biosensor has been used to detect CEA in colon and breast cancer clinical samples with satisfactory results. Therefore, the instability of BP can also be the advantage for application in detecting cancer biomarker in clinic.     

Kidney Podocytes as Specific Targets for cyclo(RGDfC)‐Modified Nanoparticles

Renal nanoparticle passage opens the door for targeting new cells like podocytes, which constitute the exterior part of the renal filter. When cyclo(RGDfC)‐modified Qdots are tested on isolated primary podocytes for selective binding to the αvβ3 integrin receptor a highly cell‐ and receptor‐specific binding can be observed. In displacement experiments with free cyclo(RGDfC) IC₅₀ values of 150 nM for αvβ3 integrin over‐expressing U87‐MG cells and 60 nM for podocytes are measured. Confocal microscopy shows a cellular Qdot uptake into vesicle‐like structures. Our ex vivo study gives clear evidence that, after renal filtration, nanoparticles can be targeted to podocyte integrin receptors in the future. This could be a highly promising approach for future therapy and diagnostics of podocyte‐associated diseases.     

PD‐1 Blockade for Improving the Antitumor Efficiency of Polymer–Doxorubicin Nanoprodrug

Chemotherapy is well recognized to induce immune responses during some chemotherapeutic drugs‐mediated tumor eradication. Here, a strategy involving blocking programmed cell death protein 1 (PD‐1) to enhance the chemotherapeutic effect of a doxorubicin nanoprodrug HA‐Psi‐DOX is proposed and the synergetic mechanism between them is further studied. The nanoprodrugs are fabricated by conjugating doxorubicin (DOX) to an anionic polymer hyaluronic acid (HA) via a tumor overexpressed matrix metalloproteinase sensitive peptide (CPLGLAGG) for tumor targeting and enzyme‐activated drug release. Once accumulated at the tumor site, the nanoprodrug can be activated to release antitumor drug by tumor overexpressed MMP‐2. It is found that HA‐Psi‐DOX nanoparticles can kill tumor cells effectively and initiate an antitumor immune response, leading to the upregulation of interferon‐γ. This cytokine promotes the expression of programmed cell death protein‐ligand 1 (PD‐L1) on tumor cells, which will cause immunosuppression after interacting with PD‐1 on the surface of lymphocytes. The results suggest that the therapeutic efficiency of HA‐Psi‐DOX nanoparticles is significantly improved when combined with checkpoint inhibitors anti‐PD‐1 antibody (α‐PD1) due to the neutralization of immunosuppression by blocking the interaction between PD‐L1 and PD‐1. This therapeutic system by combining chemotherapy and immunotherapy further increases the link between conventional tumor therapies and immunotherapy.