bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2021‒12‒19
28 papers selected by
Ceren Kimna
Technical University of Munich

  1. J Pharm Sci. 2021 Dec 11. pii: S0022-3549(21)00681-X. [Epub ahead of print]
      The successful delivery of RNA therapeutics is the gating hurdle to greater clinical translation and utility of this novel class of therapeutics. Delivery strategies today are limited and predominantly rely on lipid nanoparticles or conjugates, which can facilitate hepatic delivery but are poor for achieving uptake outside the liver. The ability to deliver RNA to other organs outside the liver in a formulation-agnostic approach could serve to unlock the broader potential of these therapies and enable their use in a broader set of disease. Here we demonstrate this formulation-agnostic delivery of two model siRNAs using low-frequency ultrasound to the gastrointestinal (GI) tract. Unformulated siRNAs targeting β-catenin (Ctnnb 1) and Sjögren syndrome antigen B (SSB) genes were successfully delivered to colonic mucosa in mice, achieving robust knockdown of the target mRNA from whole-colon tissue samples. Indeed, the capacity to target and successfully suppress expression from genes underscores the power of this platform to rapidly deliver unformulated and unoptimized sequences against a range of targets in the GI tract.
    Keywords:  Antisense Therapy; Drug Delivery; Inflammatory Bowel Disease; Mucosal Delivery; RNA; Sjögren Syndrome Antigen B; Ulcerative Colitis; Ultrasound; β-catenin
  2. Adv Mater. 2021 Dec 13. e2107150
      Ferritin (Fn) is considered a promising carrier for targeted delivery to tumors, but the successful application in vivo has not been fully achieved yet. Herein, strong evidence is provided that the Fn receptor is expressed in liver tissues, resulting in an intercept effect in regards to tumor delivery. Building on these observations, a biomineralization technology is rationally designed to shield Fn using a calcium phosphate (CaP) shell, which can improve the delivery performance by reducing Fn interception in the liver while re-exposing it in acidic tumors. Moreover, the selective dissolution of the CaP shell not only neutralizes the acidic microenvironment but also induces the intratumoral immunomodulation and calcification. Upon multiple cell line and patient-derived xenografts, it is demonstrated that the elaboration of the highly flexible Fn@CaP chassis by loading a chemotherapeutic drug into the Fn cavity confers potent antitumor effects, and additionally encapsulating a photosensitizer into the outer shell enables a combined chemo-photothermal therapy for complete suppression of advanced tumors. Altogether, these results support Fn@CaP as a new nanoplatform for efficient modulation of the tumor microenvironment and targeted delivery of diverse therapeutic agents.
    Keywords:  biomineralization; ferritin; synergistic therapy; tumor microenvironment
  3. Adv Funct Mater. 2021 Oct 08. pii: 2103600. [Epub ahead of print]31(41):
      Camouflaged cell-membrane-based nanoparticles have been gaining increasing attention owing to their improved biocompatibility and immunomodulatory properties. Using nanoparticles prepared from the membranes of specific cell types, or fusions derived from different cells membranes, can improve their functional performance in several aspects. Here, we used cell membranes extracted from breast cancer cells and platelets to fabricate a hybrid-membrane vesicle fusion (cancer cell-platelet-fusion-membrane vesicle, CPMV) in which we loaded therapeutic microRNAs (miRNAs) for the treatment of triple-negative breast cancer (TNBC). We used a clinically scalable microfluidic platform for the fusion of cell membranes. The reconstitution process during synthesis allows for efficient loading of miRNAs into CPMVs. We systematically optimized the conditions for preparation of miRNA-loaded CPMVs and demonstrated their property of homing to source cells using in vitro experiments, and by therapeutic evaluation in vivo. In vitro, the CPMVs exhibited significant recognition of their source cells and avoided engulfment by macrophages. After systemic delivery in mice, the CPMVs showed a prolonged circulation time and site-specific accumulation at implanted TNBC-xenografts. The delivered antimiRNAs sensitized TNBCs to doxorubicin, resulting in an improved therapeutic response and survival rate. This strategy has considerable potential for clinical translation to improve personalized therapy for breast cancer and other malignancies.
    Keywords:  Cancer cell-platelet membrane fusion vesicle; chemotherapy; doxorubicin; microRNAs; microfluidics; presensitization; triple-negative breast cancer
  4. Small. 2021 Dec 16. e2106296
      Checkpoint blockade immunotherapy has broad application prospects in the clinical treatment of malignant tumors. However, the low response rate of the checkpoint blockade is due to low tumor immunogenicity and immunosuppression within the tumor microenvironment. Herein, the authors design an amphiphilic bifunctional PD-1/PD-L1 peptide antagonist PCP, and co-deliver doxorubicin (DOX) and R848 through co-assembly of a multi-agent prodrug (PCP@R848/DOX), which can be specifically cleaved by fibroblast activation protein-α (FAP-α) in the tumor stroma. Upon reaching the tumor tissue, the PCP@R848/DOX prodrug nanostructure is disassembled by FAP-α. The localized release of DOX and R848 triggers immunogenic cell death (ICD) and reprograms tumor-associated macrophages (TAMs) to elicit antitumor immunity. Furthermore, sustained release of PD-1 or PD-L1 peptide antagonists mediates the PD-L1 pathway blockade for further propagated activation of cytotoxic T lymphocytes. Notably, a tumor microenvironment activatable prodrug nanoparticle is presented for triple-modality cancer therapy that functions by simultaneously activating ICD and altering the phenotype of TAMs when combined with PD-1 blockade therapy, which efficiently elicits a strong systemic antitumor immune response. This strategy may emerge as a new paradigm in the treatment of cancer by combination immunotherapy.
    Keywords:  PD-L1 peptide; cancer immunotherapy; fibroblast activation protein-α; immunogenic cell death; tumor-associated macrophage polarization
  5. Adv Mater. 2021 Dec 12. e2108525
      Increasing evidence suggests that activation of microglia-induced neuroinflammation plays a crucial role in the pathophysiology of depression. Consequently, targeting the central nervous system to reduce neuroinflammation holds great promise for the treatment of depression. However, few drugs can enter the brain via a circulatory route through the blood-brain barrier (BBB) to reach the central nervous system efficiently, which limits the pharmacological treatment for neuropsychiatric diseases. Herein, a light-responsive system named UZPM consisting of blue-emitting NaYF4 :Yb, Tm@zeolitic-imidazolate framework (UCNP@ZIF-8), photoacid (PA) and melatonin (MT) is developed to address above issues. Meanwhile, UZPM is introduced into macrophages by functional liposomes fusion and modified with hydroxylamine groups on the cell surface. Aldehyde-modified cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) is used as a chimeric antigen receptor (CAR) targeting group to modify the surface of macrophages by aldehyde/hydroxylamine condensation to precisely target central M1-type microglia (CAR-M-UZPM). Both in vitro and in vivo experiments demonstrate that the CAR-M-UZPM drug delivery system can efficiently penetrate BBB, targeting centrally activated microglia, thus, inhibiting the M1-type polarization of microglia, producing continuous vaccine-like anti-inflammatory effects that prevent the occurrence and development of inflammation-related depression. This article is protected by copyright. All rights reserved.
    Keywords:  inflammation-related depression; melatonin; membrane engineering; near-infrared light; neurological drug delivery
  6. Adv Sci (Weinh). 2021 Dec 16. e2102072
      Liposomes can efficiently deliver messenger RNA (mRNA) into cells. When mRNA cocktails encoding different proteins are needed, a considerable challenge is to efficiently deliver all mRNAs into the cytosol of each individual cell. In this work, two methods are explored to co-deliver varying ratiometric doses of mRNA encoding red (R) or green (G) fluorescent proteins and it is found that packaging mRNAs into the same lipoplexes (mingle-lipoplexes) is crucial to efficiently deliver multiple mRNA types into the cytosol of individual cells according to the pre-defined ratio. A mixture of lipoplexes containing only one mRNA type (single-lipoplexes), however, seem to follow the "first come - first serve" principle, resulting in a large variation of R/G uptake and expression levels for individual cells leading to ratiometric dosing only on the population level, but rarely on the single-cell level. These experimental observations are quantitatively explained by a theoretical framework based on the stochasticity of mRNA uptake in cells and endosomal escape of mingle- and single-lipoplexes, respectively. Furthermore, the findings are confirmed in 3D retinal organoids and zebrafish embryos, where mingle-lipoplexes outperformed single-lipoplexes to reliably bring both mRNA types into single cells. This benefits applications that require a strict control of protein expression in individual cells.
    Keywords:  cellular uptake; mingle/single-mRNA lipoplex; protein expression; single cell; theoretical modeling
  7. Nat Commun. 2021 Dec 17. 12(1): 7336
      Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with a complex microenvironment. Dichotomous tumour-promoting and -restrictive roles have been ascribed to the tumour microenvironment, however the effects of individual stromal subsets remain incompletely characterised. Here, we describe how heterocellular Oncostatin M (OSM) - Oncostatin M Receptor (OSMR) signalling reprograms fibroblasts, regulates tumour growth and metastasis. Macrophage-secreted OSM stimulates inflammatory gene expression in cancer-associated fibroblasts (CAFs), which in turn induce a pro-tumourigenic environment and engage tumour cell survival and migratory signalling pathways. Tumour cells implanted in Osm-deficient (Osm-/-) mice display an epithelial-dominated morphology, reduced tumour growth and do not metastasise. Moreover, the tumour microenvironment of Osm-/- animals exhibit increased abundance of α smooth muscle actin positive myofibroblasts and a shift in myeloid and T cell phenotypes, consistent with a more immunogenic environment. Taken together, these data demonstrate how OSM-OSMR signalling coordinates heterocellular interactions to drive a pro-tumourigenic environment in PDA.
  8. Nat Commun. 2021 Dec 14. 12(1): 7264
      Antibodies targeting costimulatory receptors of T cells have been developed for the activation of T cell immunity in cancer immunotherapy. However, costimulatory molecule expression is often lacking in tumor-infiltrating immune cells, which can impede antibody-mediated immunotherapy. Here, we hypothesize that delivery of costimulatory receptor mRNA to tumor-infiltrating T cells will enhance the antitumor effects of antibodies. We first design a library of biomimetic nanoparticles and find that phospholipid nanoparticles (PL1) effectively deliver costimulatory receptor mRNA (CD137 or OX40) to T cells. Then, we demonstrate that the combination of PL1-OX40 mRNA and anti-OX40 antibody exhibits significantly improved antitumor activity compared to anti-OX40 antibody alone in multiple tumor models. This treatment regimen results in a 60% complete response rate in the A20 tumor model, with these mice being resistant to rechallenge by A20 tumor cells. Additionally, the combination of PL1-OX40 mRNA and anti-OX40 antibody significantly boosts the antitumor immune response to anti-PD-1 + anti-CTLA-4 antibodies in the B16F10 tumor model. This study supports the concept of delivering mRNA encoding costimulatory receptors in combination with the corresponding agonistic antibody as a strategy to enhance cancer immunotherapy.
  9. Biomater Sci. 2021 Dec 14.
      Lipid nanoparticles (LNPs) have been established as an essential platform for nucleic acid delivery. Efforts have led to the development of vaccines that protect against SARS-CoV-2 infection using LNPs to deliver messenger RNA (mRNA) coding for the viral spike protein. Out of the four essential components that comprise LNPs, phospholipids represent an underappreciated opportunity for fundamental and translational study. We investigated this avenue by systematically modulating the identity of the phospholipid in LNPs with the goal of identifying specific moieties that directly enhance or hinder delivery efficacy. Results indicate that phospholipid chemistry can enhance mRNA delivery by increasing membrane fusion and enhancing endosomal escape. Phospholipids containing phosphoethanolamine (PE) head groups likely increase endosomal escape due to their fusogenic properties. Additionally, it was found that zwitterionic phospholipids mainly aided liver delivery, whereas negatively charged phospholipids changed the tropism of the LNPs from liver to spleen. These results demonstrate that the choice of phospholipid plays a role intracellularly by enhancing endosomal escape, while also driving organ tropism in vivo. These findings were then applied to Selective Organ Targeting (SORT) LNPs to manipulate and control spleen-specific delivery. Overall, selection of the phospholipid in LNPs provides an important handle to design and optimize LNPs for improved mRNA delivery and more effective therapeutics.
  10. Adv Mater. 2021 Dec 15. e2106967
      Blockade of A2A adenosine receptors (A2AR)-adenosinergic signaling shows high potency to mobilize antitumor immunity for its in-depth involvement in immune regulation of nearly all immune cells. Available A2AR inhibition strategies are mainly based on small molecules or proteins inhibitors, yet are limited by the non-specific operation as well as the off-target toxicity. Herein, we report on the first effort to design a convenient tumor-specific A2AR inhibition strategy to improve antitumor immune responses via the spatiotemporally controlled oxygen supply by virtue of a versatile photo-modulated nanoreactor. This nanoreactor, consisting of a catalase-mimicking shell (Pt nanocatalyst) and a photothermal core (polydopamine), was rationally designed for achieving the near-infrared radiation (NIR)-guided/accelerated oxygen supplementation on tumor site, and for relieving the A2AR-mediated immunosuppression without toxicity concern. Meanwhile, the NIR light could also mediate the direct photothermal ablation of tumor, and elicit immunogenic cell deaths to boost antitumor immunity. In a poorly immunogenic breast cancer model, the intravenous injection of our nanoreactor led to the improved immune response with an increased animal survival rate, and achieved the long-term immunological memory effect against tumor recurrence as well as rechallenge. This convenient nanoreactor-stimulated A2AR inhibition approach provides a versatile promising paradigm for improving these existing immunotherapies. This article is protected by copyright. All rights reserved.
    Keywords:  A2A adenosine receptor; immune checkpoint blockade; immunotherapy; nanocatalyst; tumor oxygenation
  11. Adv Mater. 2021 Dec 18. e2106994
      Fluorescent probes capable of precise detection of atherosclerosis (AS) at an early stage and fast assessment of anti-AS drugs in animal level are particularly valuable. Herein, we introduce a highly bright aggregation-induced emission (AIE) nanoprobe by regulating the substituent of rhodanine for early detection of atherosclerotic plaque and screening of anti-AS drugs in a precise, sensitive and rapid manner. With dicyanomethylene-substituted rhodanine as the electron-withdrawing unit, the AIE luminogen named TPE-T-RCN shows the highest molar extinction coefficient, the largest photoluminescence quantum yield and the most red-shifted absorption/emission spectra simultaneously as compared to the control compounds. The nanoprobes are obtained with an amphiphilic co-polymer as the matrix encapsulating TPE-T-RCN molecules, which are further surface functionalized with anti-CD47 antibody for specifically binding to CD47 overexpressed in AS plaques. Such nanoprobes allow efficient recognition of AS plaques at different stages in apolipoprotein E-deficient (apoE-/- ) mice, especially for the recognition of early-stage AS plaques prior to Micro-CT and MRI imaging. These features impel us to apply the nanoprobes in monitoring the therapeutic effects of anti-AS drugs, providing a powerful tool for anti-AS drug screening. Their potential use in targeted imaging of human carotid plaque is further demonstrated. This article is protected by copyright. All rights reserved.
    Keywords:  CD47 antibody; aggregation-induced emission; atherosclerosis; early detection; fluorescence imaging
  12. Adv Sci (Weinh). 2021 Dec 16. e2103534
      Despite the promise of tumor starvation therapies, they are often associated with nonspecific and incomplete energy blockade. Here, a novel paradigm of starvation therapy is proposed to synergize the "Zn2+ interference"-mediated glycolysis inhibition and Zn2+ -activating GLUT1 (Glucose transporter 1) tumor specific depletion for systematic energy exhaustion. It is discovered that ZIF-8 (zinc imidazolate metal-organic frameworks ) can induce abrupt intracellular Zn2+ elevation preferentially in melanoma cells, and then achieve effective glycolysis blockade through "Zn2+ interference"-triggered decrease of NAD+ and inactivation of GAPDH, making it a powerful tumor energy nanoinhibitor. Meanwhile, Zn2+ -activating DNAzymes for specifically cleaving GLUT1 mRNA is designed. This DNAzyme can only be activated under intracellular Zn2+ overloading, and then directionally cut off glucose supply, which further restrains the adaptive up-regulation of glycolytic flux after glycolysis inhibition in tumors. Afterward, DNAzymes are loaded in ZIF-8 concurrently tethered by hyaluronic acid (HA), constructing a "nanoenabled energy interrupter ". Such a rational design presents a preferential accumulation tendency to tumor sites due to the active CD44-targeting mechanisms, specifically achieves remarkable systematic energy exhaustion in melanoma cells, and affords 80.8% in tumor growth suppression without systemic toxicity in vivo. This work verifies a fascinating therapeutic platform enabling ion interference-inductive starvation strategy for effective tumor therapy.
    Keywords:  GLUT1 depletion; glycolysis inhibition; starvation therapy; systematic energy exhaustion; zinc (II) interference
  13. Nanomicro Lett. 2021 Dec 13. 14(1): 33
      Affibody molecules are small non-immunoglobulin affinity proteins, which can precisely target to some cancer cells with specific overexpressed molecular signatures. However, the relatively short in vivo half-life of them seriously limited their application in drug targeted delivery for cancer therapy. Here an amphiphilic affibody-drug conjugate is self-assembled into nanomicelles to prolong circulation time for targeted cancer therapy. As an example of the concept, the nanoagent was prepared through molecular self-assembly of the amphiphilic conjugate of ZHER2:342-Cys with auristatin E derivate, where the affibody used is capable of binding to the human epidermal growth factor receptor 2 (HER2). Such a nanodrug not only increased the blood circulation time, but also enhanced the tumor targeting capacity (abundant affibody arms on the nanoagent surface) and the drug accumulation in tumor. As a result, this affibody-based nanoagent showed excellent antitumor activity in vivo to HER2-positive ovary and breast tumor models, which nearly eradicated both small solid tumors (about 100 mm3) and large established tumors (exceed 500  mm3). The relative tumor proliferation inhibition ratio reaches 99.8% for both models.
    Keywords:  Affibody-drug conjugate; Molecular self-assembly; Nanoagent; Targeted cancer therapy
  14. Adv Ther (Weinh). 2021 Nov;4(11): 2100144
      An effective therapeutic cancer vaccine should be empowered with the capacity to overcome the immunosuppressive tumor microenvironment. Here, the authors describe a mRNA virus-mimicking vaccine platform that is comprised of a phospholipid bilayer encapsulated with a protein-nucleotide core consisting of antigen-encoding mRNA molecules, unmethylated CpG oligonucleotides and positively charged proteins. In cell culture, VLVP potently stimulated bone marrow-derived dendritic cells (BMDCs) to express inflammatory cytokines that facilitated dendritic cell (DC) maturation and promoted antigen processing and presentation. In tumor-bearing mice, VLVP treatment stimulated proliferation of antigen-specific CD8+T cells in the lymphatic organs and T cell infiltration into the tumor bed, resulting in potent anti-tumor immunity. Cytometry by time of flight (CyTOF) analysis revealed that VLVP treatment stimulated a 5-fold increase in tumor-associated CD8+DCs and a 4-fold increase in tumorinfiltrated CD8+T cells, with concurrent decreases in tumor-associated bone marrow-derived suppressor cells and arginase 1- expressing suppressive DCs. Finally, CpG oligonucleotide is an essential adjuvant for vaccine activity. Inclusion of CpG not only maximized vaccine activity but also prevented PD-1 expression in T cells, serving the dual roles as a potent adjuvant and a checkpoint blockade agent.
    Keywords:  adjuvant; cancer; immunotherapy; mRNA vaccine; virus‐like vaccine particle
  15. Adv Mater. 2021 Dec 12. e2107877
      Smart polymeric materials with dynamically tunable physico-chemical characteristics in response to changes of environmental stimuli, have received considerable attention in myriad fields. The diverse combination of their micro-/nano-structural and molecular designs creates promising and exciting opportunities for exploiting advanced smart polymeric materials. Engineering micro-/nano-structures into smart polymeric materials with elaborate molecular design enables intricate coordination between their structures and molecular-level response to cooperatively realize smart functions for practical applications. In this review, recent progresses of smart polymeric materials that combine micro-/nano-structures and molecular design to achieve designed advanced functions are highlighted. Smart hydrogels, gating membranes, gratings, milli-particles, micro-particles and microvalves are employed as typical examples to introduce their design and fabrication strategies. Meanwhile, the key roles of interplay between their micro-/nano-structures and responsive properties to realize the desired functions for their applications are emphasized. Finally, perspectives on the current challenges and opportunities of micro-/nano-structured smart polymeric materials for their future development are presented. This article is protected by copyright. All rights reserved.
    Keywords:  Stimuli-responsive materials; smart gratings; smart hydrogels; smart membranes; smart microvalves; smart particles
  16. J Crohns Colitis. 2021 Dec 16. pii: jjab223. [Epub ahead of print]
      MicroRNAs (miRNAs), small non-coding RNAs, have recently been described as crucial contributors to intestinal homeostasis. They can interact with the gut microbiota in a reciprocal manner and deeply impact the host health status, leading to several disorders when unbalanced. Inflammatory bowel disease (IBD) is a chronic inflammation of the gastrointestinal tract that co-occurs with alterations of the gut microbiota, and whose aetiology remains largely unclear. On one hand, host miRNA could be playing a relevant role in IBD pathophysiology by shaping the gut microbiota. The gut microbiome, on the other hand, may regulate the expression of host miRNAs resulting in intestinal epithelial dysfunction, altered autophagy, and immune hyperactivation. Interestingly, it has been hypothesized that their reciprocal impact may be used for therapeutic goals. This review describes the latest research and suggests mechanisms through which miRNA and intestinal microbiota, as joint actors, may participate specifically in IBD pathophysiology. Furthermore, we discuss the diagnostic power and therapeutic potential resulting from their bidirectional communication after faecal transplantation, probiotics intake, anti-miRNAs or miRNA mimics administration. The current literature is summarized in the present work in a comprehensive manner hoping to provide a better understanding of the miRNA-microbiota crosstalk and to facilitate their application in IBD.
    Keywords:  inflammatory bowel disease; microRNA; microbiota
  17. Adv Mater. 2021 Dec 15. e2106816
      Regulating hydrogel actuators with chemical reaction networks is instrumental for constructing life-inspired smart materials. Herein we engineered hydrogel actuators that are regulated by the autocatalytic front of thiols. The actuators consist of two layers. The first layer, which is regular polyacrylamide hydrogel, is in a strained conformation. The second layer, which is polyacrylamide hydrogel with disulfide crosslinks, maintains strain in the first layer. When thiols released by the autocatalytic front reduce disulfide crosslinks, the hydrogel actuates by releasing the mechanical strain in the first layer. The autocatalytic front is sustained by the reaction network, which uses thiouronium salts, disulfides of β-aminothiols, and maleimide as starting components. The gradual actuation by the autocatalytic front enables movements such as gradual unrolling, screwing, and sequential closing of "fingers". This actuation also allows the transmission of chemical signals in a relay fashion and the conversion of a chemical signal to an electrical signal. Locations and times of spontaneous initiation of autocatalytic fronts can be preprogrammed in the spatial distribution of the reactants in the hydrogel. To approach the functionality of living matter, the actuators triggered by an autocatalytic front can be integrated into smart materials regulated by chemical circuits. This article is protected by copyright. All rights reserved.
    Keywords:  actuators; autocatalysis; hydrogels; reaction-diffusion; thiols
  18. ACS Appl Mater Interfaces. 2021 Dec 15.
      Injection of a hydrogel loaded with drugs with simultaneous anti-inflammatory and tissue regenerating properties can be an effective treatment for promoting periodontal regeneration in periodontitis. Nevertheless, the design and preparation of an injectable hydrogel with self-healing properties for tunable sustained drug release is still highly desired. In this work, polysaccharide-based hydrogels were formed by a dynamic cross-linked network of dynamic Schiff base bonds and dynamic coordination bonds. The hydrogels showed a quick gelation process, injectability, and excellent self-healing properties. In particular, the hydrogels formed by a double-dynamic network would undergo a gel-sol transition process without external stimuli. And the gel-sol transition time could be tuned by the double-dynamic network structure for in situ stimuli involving a change in its own molecular structure. Moreover, the drug delivery properties were also tunable owing to the gel-sol transition process. Sustained drug release characteristics, which were ascribed to a diffusion process, were observed during the first stage of drug release, and complete drug release owing to the gel-sol transition process was achieved. The sustained drug release time could be tuned according to the double-dynamic bonds in the hydrogel. The CCK-8 assay was used to evaluate the cytotoxicity, and the result showed no cytotoxicity, indicating that the injectable and self-healing hydrogels with double-dynamic bond tunable gel-sol transition could be safely used in controlled drug delivery for periodontal disease therapy. Finally, the promotion of periodontal regeneration in periodontitis in vivo was investigated using hydrogels loaded with ginsenoside Rg1 and amelogenin. Micro-CT and histological analyses indicated that the hydrogels were promising candidates for addressing the practical needs of a tunable drug delivery method for promoting periodontal regeneration in periodontitis.
    Keywords:  anti-inflammatory therapy; double-dynamic bond tunable drug delivery; injectable hydrogel; promoting periodontal regeneration; self-healing
  19. Adv Mater. 2021 Dec 16. e2107809
      Microscale laser emissions have emerged as a promising approach for information encoding and anticounterfeiting for their feature-rich spectra and high sensitivity to surrounding environment. Compared with artificial materials, natural responsive biomaterials enable a higher level of complexity and versatile ways for tailoring optical responses. However, precise control of lasing wavelengths and spatial locations with biomolecules remains a huge challenge. Here, we developed a biological programmable laser, in which lasing could be manipulated by biomolecular activities at the nanoscale. Tunable lasing wavelengths were achieved by exploiting swelling properties of enzyme-responsive hydrogel droplets in a Fabry-Pérot microcavity. Both experimental and theoretical means demonstrate that inner 3D network structures and external curvature of hydrogel droplets lead to different lasing thresholds and resonance wavelengths. Finally, inkjet-printed multiwavelength laser encoding and anticounterfeiting were showcased under different scalability and environment. Hyperspectral laser images were utilized as an advanced feature for higher level of security. The biological encoded laser will provide a new insight into the development of bio-synthetic and bio-programmable laser devices, offering new opportunities for secure communication and smart sensing. This article is protected by copyright. All rights reserved.
    Keywords:  anticounterfeiting; biolaser; enzyme-responsive hydrogel; laser encoding; microlaser array
  20. Adv Mater. 2021 Dec 16. e2108607
      Dysnatremia, a disorder in the concentration of sodium levels, possesses a clinical challenge leading to adverse health complications. Using biosensors for online sodium monitoring can be a promising approach to overcome this condition. In this regard, biosensors based on field-effect transistors (FETs) have promising advantages, including high sensitivity, quick response, and easy fabrication. Most of the currently developed FET designs are used only for sensing sweat and in-vitro blood/interstitial fluids (ISF). Using ISF for online detection of biomarkers and long-term health monitoring with FETs has not yet been fully resolved. Herein we propose an innovative stretchable skin-conformal fast-response microneedle extended-gate FET (MN-EGFET) biosensor for real-time detection of sodium in the ISF for minimally invasive health monitoring along with high sensitivity, low limit of detection, excellent biocompatibility, and on-body mechanical stability. This platform can, furthermore, be integrated with wireless-data transmitter and the Internet-of-Things (IoT) cloud for real-time monitoring and long-term analysis. This article is protected by copyright. All rights reserved.
    Keywords:  extended gate; field-effect transistor; interstitial fluid; microneedle; wearable sensor
  21. Adv Sci (Weinh). 2021 Dec 16. e2103999
      Upper tract urothelial carcinomas (UTUCs) are rare entities that are usually diagnosed at advanced stages. Research on UTUC pathobiology and clinical management has been hampered by the lack of models accurately reflecting disease nature and diversity. In this study, a modified organoid culture system is used to generate a library of 25 patient-derived UTUC organoid lines retaining the histological architectures, marker gene expressions, genomic landscapes, and gene expression profiles of their parental tumors. The study demonstrates that the responses of UTUC organoids to anticancer drugs can be identified and the model supports the exploration of novel treatment strategies. This work proposes a modified protocol for generating patient-derived UTUC organoid lines that may help elucidate UTUC pathophysiology and assess the responses of these diseases to various drug therapies in personalized medicine.
    Keywords:  drug screening; organoid; tumor heterogeneity; upper tract urothelial carcinoma
  22. Bioengineered. 2021 Dec;12(2): 12383-12393
      The potential of antibodies, especially for the bispecific antibodies, are limited by high cost and complex technical process of development and manufacturing. A cost-effective and rapid platform for the endogenous antibodies expression via using the in vitro transcription (IVT) technique to produce nucleoside-modified mRNA and then encapsulated into lipid nanoparticle (LNP) may turn the body to a manufactory. Coinhibitory pathway of programmed death ligand 1 (PD-L1) and programmed cell death protein 1 receptor (PD-1) could suppress the T-cell mediated immunity. We hypothesized that the coblocking of PD-L1 and PD-1 via bispecific antibodies may achieve more potential antitumor efficacies compare with the monospecific ones. Here, we described the application of mRNA to encode a bispecific antibody with ablated Fc immune effector functions that targets both human PD-L1 and PD-1, termed XA-1, which was further assessed the in vitro functional activities and in vivo antitumor efficacies. The in vitro mRNA-encoded XA-1 held comparable abilities to fully block the PD-1/PD-L1 pathway as well as to enhance functional T cell activation compared to XA-1 protein from CHO cell source. Pharmacokinetic tests showed enhanced area under curve (AUC) of mRNA-encoded XA-1 compared with XA-1 at same dose. Chronic treatment of LNP-encapsulated XA-1 mRNA in the mouse tumor models which were reconstituted with human immune cells effectively induced promising antitumor efficacies compared to XA-1 protein. Current results collectively demonstrated that LNP-encapsulated mRNA represents the viable delivery platform for treating cancer and hold potential to be applied in the treatment of many diseases.Abbreviations: IVT: in vitro transcription; LNP: lipid nanoparticle; hPD-1: human PD-1; hPD-L1: human PD-L1; ITS-G: Insulin-Transferrin-Selenium; Pen/Strep: penicillin-streptomycin; FBS: fetal bovine serum; TGI: tumor growth inhibition; IE1: cytomegalovirus immediate early 1; SP: signal peptide; hIgLC: human immunoglobulin kappa light chain; hIgHC: human IgG1 heavy chain; AUC: area under the curve; Cl: serum clearance; Vss: steady-state distributed volume; MLR: mixed lymphocyte reaction.
    Keywords:  LNP; PD-1; PD-L1; bispecific antibody; cancer immunotherapy; mRNA
  23. Adv Mater. 2021 Dec 13. e2107560
      The clinical employment of cisplatin (CDDP) is largely constrained due to the non-specific delivery and resultant serious systemic toxicity. Small-sized biocompatible and biodegradable hollow mesoporous organosilica (HMOS) nanoparticles show superior advantages for targeted CDDP delivery but suffer from premature CDDP leakage. Herein, we make the smart use of a bimetallic Zn2+ /Cu2+ co-doped metal-organic framework (MOF) to block the pores of HMOS for preventing potential leakage of CDDP and remarkably increasing the loading capacity of HMOS. Once reaching the acidic tumor microenvironment (TME), the outer MOF can decompose quickly to release CDDP for chemotherapy against cancer. Besides, the concomitant release of dopant Cu2+ can deplete the intracellular glutathione (GSH) for increased toxicity of CDDP as well as catalyzing the decomposition of intratumoral H2 O2 into highly toxic •OH for chemodynamic therapy (CDT). Moreover, the substantially reduced GSH can also protect the yielded •OH from scavenging and thus greatly improve the •OH-based CDT effect. In addition to providing a hybrid HMOS@MOF nanocarrier, this study is also expected to establish a new form of TME-unlocked nanoformula for highly efficient tumor-specific GSH depletion-enhanced synergistic chemo-chemodynamic therapy. This article is protected by copyright. All rights reserved.
    Keywords:  controllable release; mesoporous organosillica; metal-organic framework; synergistic therapy; tumor microenvironment
  24. ACS Appl Mater Interfaces. 2021 Dec 14.
      Overuse of antibiotics can increase the risk of notorious antibiotic resistance in bacteria, which has become a growing public health concern worldwide. Featured with the merit of mechanical rupture of bacterial cells, the bioinspired nanopillars are promising alternatives to antibiotics for combating bacterial infections while avoiding antibacterial resistance. However, the resident dead bacterial cells on nanopillars may greatly impair their bactericidal capability and ultimately impede their translational potential toward long-term applications. Here, we show that the functions of bactericidal nanopillars can be significantly broadened by developing a hybrid thermoresponsive polymer@nanopillar-structured surface, which retains all of the attributes of pristine nanopillars and adds one more: releasing dead bacteria. We fabricate this surface through coaxially decorating mechano-bactericidal ZnO nanopillars with thermoresponsive poly(N-isopropylacrylamide) (PNIPAAm) brushes. Combining the benefits of ZnO nanopillars and PNIPAAm chains, the antibacterial performances can be controllably regulated between ultrarobust mechano-bactericidal action (∼99%) and remarkable bacteria-releasing efficiency (∼98%). Notably, both the mechanical sterilization against the live bacteria and the controllable release for the pinned dead bacteria solely stem from physical actions, stimulating the exploration of intelligent structure-based bactericidal surfaces with persistent antibacterial properties without the risk of triggering drug resistance.
    Keywords:  antibiotic resistance; bacteria release; mechano-bactericidal; nanostructures; thermoresponsive
  25. Adv Healthc Mater. 2021 Dec 16. e2102016
      Polyplex for mRNA delivery requires strong yet reversible association between mRNA and polycation for extracellular robustness and selective intracellular disintegration. Herein, RNA oligonucleotide (OligoRNA) derivatives that bridge mRNA and polycation are developed to stabilize polyplex micelles (PMs). A set of the OligoRNAs introduced with a polyol moiety in their 5' end is designed to hybridize to fixed positions along mRNA strand. After PM preparation from the hybridized mRNA and poly(ethylene glycol) (PEG)-polycation block copolymer derivatized with phenylboronic acid (PBA) moieties in its cationic segment, PBA moieties form reversible phenylboronate ester linkages with a polyol moiety at 5' end of OligoRNAs and a diol moiety at their 3' end ribose, in the PM core. The OligoRNAs work as a node to bridge ionically complexed mRNA and polycation, thereby improving PM stability against polyion exchange reaction and ribonuclease attack in extracellular environment. After cellular uptake, intracellular high concentration of adenosine triphosphate (ATP) triggers the cleavage of phenylboronate ester linkages, resulting in mRNA release from PM. Ultimately, the PM provides efficient mRNA introduction in cultured cells and mouse lungs after intratracheal administration, demonstrating the potential of the bridging strategy in polyplex-based mRNA delivery. This article is protected by copyright. All rights reserved.
    Keywords:  ATP-responsiveness; Block copolymer; Phenylboronic acid; Polyplex micelle; mRNA delivery; mRNA engineering
  26. Front Immunol. 2021 ;12 785222
      While neutrophil extracellular traps (NETs) are important for directly promoting cancer growth, little is known about their impact on immune cells within the tumor microenvironment (TME). We hypothesize that NETs can directly interact with infiltrating T cells to promote an immunosuppressive TME. Herein, to induce a NET-rich TME, we performed liver Ischemia/Reperfusion (I/R) in an established cancer metastasis model or directly injected NETs in subcutaneous tumors. In this NET-rich TME, the majority of CD4+ and CD8+ tumor infiltrating lymphocytes expressed multiple inhibitory receptors, in addition these cells showed a functional and metabolic exhausted phenotype. Targeting of NETs in vivo by treating mice with DNAse lead to decreased tumor growth, decreased NET formation and higher levels of functioning T cells. In vitro, NETs contained the immunosuppressive ligand PD-L1 responsible for T cell exhaustion and dysfunction; an effect abrogated by using PD-L1 KO NETs or culturing NETs with PD-1 KO T cells. Furthermore, we found elevated levels of sPDL-1 and MPO-DNA, a NET marker, in the serum of patients undergoing surgery for colorectal liver metastases resection. Neutrophils isolated from patients after surgery were primed to form NETs and induced exhaustion and dysfunction of human CD4+ and CD8+ T cells. We next targeted PD-L1 in vivo by injecting a blocking antibody during liver I/R. A single dose of anti-PD-L1 during surgery lead to diminished tumors at 3 weeks and functional T cells in the TME. Our data thus reveal that NETs have the capability of suppressing T cell responses through metabolic and functional exhaustion and thereby promote tumor growth. Furthermore, targeting of PD-L1 containing NETs at time of surgery with DNAse or anti-PD-L1 lead to diminished tumor growth, which represents a novel and viable strategy for sustaining immune competence within the TME.
    Keywords:  PD-L1; T cell dysfunction; T cell exhaustion; neutrophil extracellular traps; program death-ligand 1; tumor microenvironment
  27. Int J Pharm. 2021 Dec 14. pii: S0378-5173(21)01162-5. [Epub ahead of print] 121356
      PURPOSE: Drug-resistant gram-negative bacteria have emerged as a global crisis. Therefore, novel antibiotics and novel anti-infection strategies are urgently needed. Current antibiotics remain unsatisfactory due to poor targeting efficiency and poor drug penetration through the bacterial cell wall. Thus, targeted delivery of antibiotics into gram-negative bacteria should be a promising approach. Moreover, gram-negative bacteria can release lipopolysaccharide (LPS) to induce inflammatory response and septic shock, further increasing the disease burden. Hence, it is also promising to neutralize LPS while delivering antibiotics. This study aims to develop a multifunctional bacteria-targeting liposome that could enhance the delivery of antibiotics and adsorb LPS.METHODS: A polymyxin B (PMB)-modified liposomal system (P-Lipo) was developed as novel carrier of cinnamaldehyde (CA) by using a thin-film evaporation method. Liposome morphology, size, zeta potential, stability, entrapment efficiency, and in vitro release were systematically evaluated. The bacteria-targeting effect and LPS-neutralizing capacity of P-Lipo were evaluated both in vitro and in vivo. The antibacterial effect of CA-loaded P-Lipo was assessed in Escherichia coli (E. coli) O157:H7 and Pseudomonas aeruginosa (P. aeruginosa). Ultimately, the therapeutic effect of P-CA-Lipo was investigated in E. coli O157:H7-infected mice.
    RESULTS: P-Lipo was successfully synthesized and encapsulated with CA, which was well characterized. Both in vivo and in vitro experiments demonstrated that P-Lipo could efficiently target the E. coli after modification with PMB. Compared with free CA, CA-Lipo, and P-Lipo, P-CA-Lipo exhibited a significantly enhanced inhibitory effect on E. coli and P.aeruginosa. Further analysis demonstrated that P-CA-Lipo improved the bacterial uptake of CA and enhanced its antibacterial effect. It was also confirmed that P-Lipo could neutralize the LPS to avoid the inflammatory responses and inhibit the release of proinflammatory cytokines in both macrophages and mice. Finally, P-CA-Lipo inhibited E. coli-induced skin damage and death in mice and showed good biocompatibility.
    CONCLUSION: The P-Lipo could target E. coli by binding with LPS and enhancing the delivery and internalization of CA. In addition, P-Lipo could adsorb free LPS synergistically, thus promoting the infection management. We believe that this strategy can provide innovative insights into antibacterial agent delivery for the treatment of persistent and severe bacterial infections.
    Keywords:  Polymyxin B; bacterial infection; cinnamaldehyde; lipopolysaccharide; liposome
  28. Proc Natl Acad Sci U S A. 2021 12 28. pii: e2116668118. [Epub ahead of print]118(52):
      Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease (COVID-19), continues to be a pressing health concern. In this study, we investigated the impact of SARS-CoV-2 infection on host microRNA (miRNA) populations in three human lung-derived cell lines, as well as in nasopharyngeal swabs from SARS-CoV-2-infected individuals. We did not detect any major and consistent differences in host miRNA levels after SARS-CoV-2 infection. However, we unexpectedly discovered a viral miRNA-like small RNA, named CoV2-miR-O7a (for SARS-CoV-2 miRNA-like ORF7a-derived small RNA). Its abundance ranges from low to moderate as compared to host miRNAs and it associates with Argonaute proteins-core components of the RNA interference pathway. We identify putative targets for CoV2-miR-O7a, including Basic Leucine Zipper ATF-Like Transcription Factor 2 (BATF2), which participates in interferon signaling. We demonstrate that CoV2-miR-O7a production relies on cellular machinery, yet is independent of Drosha protein, and is enhanced by the presence of a strong and evolutionarily conserved hairpin formed within the ORF7a sequence.
    Keywords:  SARS-CoV-2; micoRNA; noncoding RNA