bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2022‒05‒08
25 papers selected by
Ceren Kimna
Technical University of Munich

  1. ACS Nano. 2022 May 02.
      The protein corona is a protein layer formed on the surface of nanoparticles administered in vivo and considerably affects the in vivo fate of nanoparticles. Although it is challenging to control protein adsorption on nanoparticles precisely, the protein corona may be harnessed to develop a targeted drug delivery system if the nanoparticles are decorated with a ligand with enhanced affinity to target tissue- and cell-homing proteins. Here, we prepared a DNA tetrahedron with trivalent cholesterol conjugation (Chol3-Td) that can induce enhanced interaction with lipoproteins in serum, which in situ generates the lipoprotein-associated protein corona on a DNA nanostructure favorable for cells abundantly expressing lipoprotein receptors in the liver, such as hepatocytes in healthy mice and myofibroblasts in fibrotic mice. Chol3-Td was further adopted for liver delivery of antisense oligonucleotide (ASO) targeting TGF-β1 mRNA to treat liver fibrosis in a mouse model. The potency of ASO@Chol3-Td was comparable to that of ASO conjugated with the clinically approved liver-targeting ligand, trivalent N-acetylgalactosamine (GalNAc3), demonstrating the potential of Chol3-Td as a targeted delivery system for oligonucleotide therapeutics. This study suggests that controlled seeding of the protein corona on nanomaterials can provide a way to steer nanoparticles into the target area.
    Keywords:  DNA tetrahedron; cholesterol conjugation; liver delivery; oligonucleotide therapeutics; protein corona; targeted delivery
  2. J Control Release. 2022 Apr 27. pii: S0168-3659(22)00233-4. [Epub ahead of print]
      Osteoarthritis (OA) is a chronic disease caused by joint inflammation. Its occurrence and development depend on a continuous inflammation environment. The activated M1 macrophages play a critical role in the inflammatory response of OA. Regulating the pro-inflammatory M1 to anti-inflammatory M2 macrophages in the OA articular cavity could be a rational strategy for OA treatment. It has been acknowledged that activated macrophages could proactively capture opsonized nanoparticles in the bloodstream and then accumulate into the reticuloendothelial system (RES) organs. Based on this fact, a trapping strategy is proposed, which transforms a normal nanoparticle into an opsonized attractant to target and regulate macrophage polarization. In this study, the opsonized nanoparticle (IgG/Bb@BRPL) had several key features, including an immunoglobulin IgG (the opsonized layer), an anti-inflammatory agent berberine (Bb), and an oxidative stress-responsive bilirubin grafted polylysine biomaterial (BR-PLL) for drug loading (the inner nanocore). In vitro studies confirmed that IgG/Bb@BRPL prefer to be phagocytosed by M1 macrophage, not M0. And the internalized IgG/Bb@BRPL effectively promoted macrophage polarization toward the M2 phenotype and protected nearby chondrocytes. In vivo studies suggested that IgG/Bb@BRPL significantly enhanced therapeutic outcomes by suppressing inflammation and promoting cartilage repair while not prolonging the retention period compared to non-opsonized counterparts. This proof-of-concept study provided a novel opsonization trapping strategy for OA drug delivery and treatment.
    Keywords:  Cartilage; Inflammatory; Macrophages; Opsonized nanoparticle; Osteoarthritis
  3. ACS Nano. 2022 May 01.
      The inability of commercial personal protective equipment (PPE) to inactivate microbes in the droplets/aerosols they intercept makes used PPE a potential source of cross-contamination. To make PPE spontaneously and continuously antimicrobial, we incorporate PPE with oxidase-like catalysts, which efficiently convert O2 into reactive oxygen species (ROS) without requiring any externally applied stimulus. Using a single-atom catalyst (SAC) nanoparticle containing atomically dispersed copper atoms as the reactive centers (Cu-SAC) and a silver-palladium bimetallic alloy nanoparticle (AgPd0.38) as models for oxidase-like catalysts, we show that the incorporation of oxidase-like catalysts enables PPE to inactivate bacteria in the droplets/aerosols they intercept without requiring any externally applied stimulus. Notably, this approach works both for PPE that are fibrous and woven such as a commercial KN95 facial respirator and for those made of solid plastics such as an apron. This work suggests a feasible and global approach for preventing PPE from spreading infectious diseases.
    Keywords:  antimicrobial; catalysts; infectious disease; personal protective equipment; reactive oxygen species
  4. Adv Sci (Weinh). 2022 May 07. e2200477
      New strategies to decrease risk of relapse after surgery are needed for improving 5-year survival rate of hepatocellular carcinoma (HCC). To address this need, a wound-targeted nanodrug is developed, that contains an immune checkpoint inhibitor (anti-PD-L1)and an angiogenesis inhibitor (sorafenib)). These nanoparticles consist of highly biocompatible mesoporous silica (MSNP) that is surface-coated with platelet membrane (PM) to achieve surgical site targeting in a self-amplified accumulation manner. Sorafenib is introduced into the MSNP pores while covalently attaching anti-PD-L1 antibody on the PM surface. The resulting nano-formulation, abbreviated as a-PM-S-MSNP, can effectively target the surgical margin when intraperitoneally (IP) administered into an immune competent murine orthotopic HCC model. Multiple administrations of a-PM-S-MSNP generate potent anti-HCC effect and significantly prolong overall mice survival. Immunophenotyping and immunochemistry staining reveal the signatures of favorable anti-HCC immunity and anti-angiogenesis effect at tumor sites. More importantly, microscopic inspection of a-PM-S-MSNP treated mice shows that 2 out 6 are histologically tumor-free, which is in sharp contrast to the control mice where tumor foci can be easily identified. The data suggest that a-PM-S-MSNP can efficiently inhibit post-surgical HCC relapse without obvious side effects and holds considerable promise for clinical translation as a novel nanodrug.
    Keywords:  combination therapy; hepatocellular carcinoma recurrence; mesoporous silica nanoparticle; platelet membrane
  5. Adv Mater. 2022 May 05. e2201731
      Tetrahedral framework nucleic acids (tFNAs) have attracted extensive attention as drug nanocarriers because of their excellent cellular uptake. However, for oligonucleotide cargos, tFNA mainly acts as a static delivery platform generated via sticky-ended ligation. Here, inspired by the original stable space inside the tetrahedral scaffold, we fabricate a dynamic lysosome-activated tFNA nanobox for completely encapsulating a short interfering RNA (siRNA) of interest. The closed tetrahedral structure endows cargo siRNA with greater resistance against RNase and serum and enables solid integration with the vehicle during delivery. Moreover, the pH-responsive switch of nanobox allows the controlled release of siRNA upon entry into lysosomes at cell culture temperature. Based on protective loading and active unloading, an excellent silencing effect on the target TNFα gene was achieved in vitro and in vivo experiments. Conclusively, nanobox offers a dynamic pH-sensitive confinement delivery system for siRNA and can be an extendable strategy for other small RNA. This article is protected by copyright. All rights reserved.
    Keywords:  DNA nanotechnology; framework nucleic acids; lysosome activating; pH responsiveness; siRNA delivery
  6. Nat Biomed Eng. 2022 May 02.
      The complex gastrointestinal environment and the intestinal epithelial barrier constrain the design and effectiveness of orally administered tumour vaccines. Here we show that outer membrane vesicles (OMVs) fused to a tumour antigen and produced in the intestine by ingested genetically engineered bacteria function as effective tumour vaccines in mice. We modified Escherichia coli to express, under the control of a promoter induced by the monosaccharide arabinose, a specific tumour antigen fused with the protein cytolysin A on the surface of OMVs released by the commensal bacteria. In mice, oral administration of arabinose and the genetically engineered E. coli led to the production of OMVs that crossed the intestinal epithelium into the lamina propria, where they stimulated dendritic cell maturation. In a mouse model of pulmonary metastatic melanoma and in mice bearing subcutaneous colon tumours, the antigen-bearing OMVs inhibited tumour growth and protected the animals against tumour re-challenge. The in situ production of OMVs by genetically modified commensal bacteria for the delivery of stimulatory molecules could be leveraged for the development of other oral vaccines and therapeutics.
  7. ACS Nano. 2022 May 03.
      Phototheranostics is a potential area for precision medicine, which has received increasing attention for antibacterial applications. Integrating all phototheranostic modalities in a single molecule and achieving precise spatial colocalization is a challenging task because of the complexity of energy dissipation and molecular design. Here, a type of quaternary amine functionalized aggregation-induced emission (AIE), AIEgen, was synthesized and used to produce singlet oxygen (1O2) and heat, which were used to eradicate the bacteria. With the introduction of the positive charge in AIEgen, AIE nanoparticles (AIE NPs) could selectively target bacteria. Notably, the AIE NPs displayed obvious antibacterial performance against Gram-positive bacteria (Staphylococcus aureus) and Gram-negative bacteria (Escherichia coli). The antibacterial rates of AIE NPs were as high as 99.9% and 99.8% for S. aureus and E. coli, respectively. Therefore, our results suggested the potential of AIE NPs acting as broad-spectrum antimicrobial materials, which provided a strategy for treating different microorganisms.
    Keywords:  aggregation-induced emission; antibacterial performance; photodynamic therapy; phototheranostics; photothermal therapy; singlet oxygen
  8. Adv Sci (Weinh). 2022 May 04. e2200608
      The numerous biological barriers, which limit pharmacotherapy of pancreatic carcinoma, including inadequate drug accumulation in the tumor environment, a dense extracellular matrix (ECM) and efficient drug-efflux mechanisms, illustrate the requirement of multifunctional delivery systems to overcome the individual barriers at the right place at the right time. Herein, a space-time conversion vehicle based on covalent organic framework (COF)-coated mesoporous silica nanospheres (MSN) with a sandwiched polyethyleneimine (PEI) layer (MPCP), is designed. The space-specific drugs-loaded vehicle (MG PP CL P) is obtained by separately incorporating a chemotherapeutic agent (gemcitabine, G) into the MSN core, a P glycoprotein inhibitor (LY 335979, P) into the PEI layer, and an extracellular matrix disruptor (losartan, L) into the COF shell. Thereafter, a programmed drug delivery is achieved via the ordered degradation from COF shell to MSN core. Sequential release of the individual drugs, synergized with a change of nanoparticle surface charge, contribute to an obvious extracellular matrix distraction, distinct drug efflux inhibition, and consequently enhance chemotherapeutic outcomes in pancreatic carcinoma. This MPCP-based vehicle design suggests a robust space-time conversion strategy to achieve programmed multi-drugs delivery and represents a new avenue to the treatment of pancreatic carcinoma by overcoming extracellular matrix and drug reflux barriers.
    Keywords:  covalent organic framework; multi-drugs delivery; pancreatic carcinoma; programmed drug delivery
  9. Nano Lett. 2022 May 06.
      Nucleic-acid-based immune adjuvants have been extensively investigated for the design of cancer vaccines. However, nucleic acids often require the assistance of a carrier system to improve cellular uptake. Yet, such systems are prone to carrier-associated adaptive immunity, leading to difficulties in a multidose treatment regimen. Here, we demonstrate that a spherical nucleic acid (SNA)-based self-adjuvanting system consisting of phosphodiester oligonucleotides and vitamin E can function as a potent anticancer vaccine without a carrier. The two functional modules work synergistically, serving as each other's delivery vector to enhance toll-like receptor 9 activation. The vaccine rapidly enters cells carrying OVA model antigens, which enables efficient activation of adaptive immunity in vitro and in vivo. In OVA-expressing tumor allograft models, both prophylactic and therapeutic vaccinations significantly retard tumor growth and prolong animal survival. Furthermore, the vaccinations were also able to reduce lung metastasis in a B16F10-OVA model.
    Keywords:  CpG oligonucleotides; DNA amphiphiles; cancer vaccines; spherical nucleic acids
  10. Nano Lett. 2022 May 06.
      Physiological microenvironment engineering has shown great promise in combating a variety of diseases. Herein, we present the rational design of reinforced and injectable blood-derived protein hydrogels (PDA@SiO2-PRF) composed of platelet-rich fibrin (PRF), polydopamine (PDA), and SiO2 nanofibers that can act as dual-level regulators to engineer the microenvironment for personalized bone regeneration with high efficacy. From the biophysical level, PDA@SiO2-PRF with high stiffness can withstand the external loading and maintaining the space for bone regeneration in bone defects. Particularly, the reinforced structure of PDA@SiO2-PRF provides bone extracellular matrix (ECM)-like functions to stimulate osteoblast differentiation via Yes-associated protein (YAP) signaling pathway. From the biochemical level, the PDA component in PDA@SiO2-PRF hinders the fast degradation of PRF to release autologous growth factors in a sustained manner, providing sustained osteogenesis capacity. Overall, the present study offers a dual-level strategy for personalized bone regeneration by engineering the biophysiochemical microenvironment to realize enhanced osteogenesis efficacy.
    Keywords:  biophysiochemical microenvironments; bone regeneration; dual-level regulation; personalized medicine; reinforced blood-derived protein hydrogels
  11. ACS Nano. 2022 May 06.
      Nucleated protein self-assembly of an azido modified spider silk protein was employed in the preparation of nanofibrillar networks with hydrogel-like properties immobilized on coatings of the same protein. Formation of the networks in a mild aqueous environment resulted in thicknesses between 2 and 60 nm, which were controlled only by the protein concentration. Incorporated azido groups in the protein were used to "click" short nucleic acid sequences onto the nanofibrils, which were accessible to specific hybridization-based modifications, as proved by fluorescently labeled DNA complements. A lipid modifier was used for efficient incorporation of DNA into the membrane of nonadherent Jurkat cells. Based on the complementarity of the nucleic acids, highly specific DNA-assisted immobilization of the cells on the nanohydrogels with tunable cell densities was possible. Addressability of the DNA cell-to-surface anchor was demonstrated with a competitive oligonucleotide probe, resulting in a rapid release of 75-95% of cells. In addition, we developed a photolithography-based patterning of arbitrarily shaped microwells, which served to spatially define the formation of the nanohydrogels. After detaching the photoresist and PEG-blocking of the surface, DNA-assisted immobilization of the Jurkat cells on the nanohydrogel microstructures was achieved with high fidelity.
    Keywords:  DNA modification; cells; nanofibrils; nanohydrogels; patterning; self-assembly; surfaces
  12. Adv Mater. 2022 May 06. e2203246
      Despite the great promises of sonodynamic therapy (SDT) in combination cancer therapy, its clinical applications are hindered by the lack of efficient sonosensitizers and "always-on" pharmacological activities of therapeutic agents. Herein, we report the development of semiconducting polymers as efficient sonosensitizers and further development of sono-immunotherapeutic nanobodies (SPNAb ) for activatable cancer sono-immunotherapy. Conjugation of anti-CTLA-4 antibodies onto the polymer nanoparticles through 1 O2 -cleavable linker affords SPNAb with relatively low CTLA-4 binding affinity. Upon sono-irradiation, SPNAb generates 1 O2 not only to elicit sonodynamic effect to induce the immunogenic cell death, but also to release anti-CTLA-4 antibodies and trigger in situ checkpoint blockade. Such a synergistic therapeutic action mediated by SPNAb modulates the tumoricidal function of T-cell immunity by promoting the proliferation of cytotoxic T lymphocytes and depleting immunosuppressive regulatory T cells, resulting in effective tumor regression, metastasis inhibition, durable immunological memory, and prevention of relapse. Therefore, this study represents a proof-of-concept sonodynamic strategy using semiconducting polymers for precise spatiotemporal control over immunotherapy. This article is protected by copyright. All rights reserved.
    Keywords:  Organic nanoparticles; cancer therapy; immunotherapy; sonodynamic therapy
  13. Adv Sci (Weinh). 2022 May 07. e2200281
      Emerging evidence indicates that a vicious cycle between inflammation and microthrombosis catalyzes the pathogenesis of inflammatory bowel disease (IBD). Over-stimulated inflammation triggers a coagulation cascade and leads to microthrombosis, which further complicates the injury through tissue hypoxia and ischemia. Herein, an injectable protein hydrogel with anti-thrombosis and anti-inflammation competency is developed to impede this cycle, cross-linked by silver ion mediated metal-ligand coordination and electronic interaction with sulfhydryl functionalized bovine serum albumin and heparin, respectively. The ex vivo experiments show that the hydrogel, HEP-Ag-BSA, exhibits excellent self-healing ability, injectability, biocompatibility, and sustained drug release. HEP-Ag-BSA also demonstrates anti-coagulation and anti-inflammation abilities via coagulation analysis and lipopolysaccharide stimulation assay. The in vivo imaging confirms the longer retention time of HEP-Ag-BSA at inflammatory sites than in normal mucosa owing to electrostatic interactions. The in vivo study applying a mouse model with colitis also reveals that HEP-Ag-BSA can robustly inhibit inflammatory microthrombosis with reduced bleeding risk. This versatile protein hydrogel platform can definitively hinder the "inflammation and microthrombosis" cycle, providing a novel integrated approach against IBD.
    Keywords:  inflammatory bowel disease; microthrombosis; protein hydrogel
  14. Small. 2022 May 06. e2200824
      Constructing high-order DNA nano-architectures in large sizes is of critical significance for the application of DNA nanotechnology. Robust and flexible design strategies together with easy protocols to construct high-order large-size DNA nano-architectures remain highly desirable. In this work, the authors report a simple and versatile one-pot strategy to fabricate DNA architectures with the assistance of spherical gold nanoparticles modified with thiolated oligonucleotide strands (SH-DNA-AuNPs), which serve as "power strips" to connect various DNA nanostructures carrying complementary ssDNA strands as "plugs". By modulating the plug numbers and positions on each DNA nanostructure and the ratios between DNA nanostructures and AuNPs, the desired architectures are formed via the stochastic co-assembly of different modules. This SH-DNA-AuNP-mediated plug-in assembly (SAMPA) strategy offers new opportunities to drive macroscopic self-assembly to meet the demand of the fabrication of well-defined nanomaterials and nanodevices.
    Keywords:  DNA origami; DNA tiles; gold nanoparticles; nano-architectures; self-assembly
  15. Adv Mater. 2022 May 02. e2201914
      Shape memory polymers (SMPs) induced by heat or water are commonly used candidates for biomedical applications. Shape recovery inevitably leads to a dramatic decrease of Youngs modulus due to the enhanced flexibility of polymer chains at the transition temperature. Herein, we introduced the principle of phase transition-induced stiffening of shape memory metallic alloys (SMAs) to the design of molecular structures for shape memory polyurethane (SMPUs), featuring all hard segments composed main chains that are attached with poly(ethylene glycol) (PEG) dangling side chains. Different from conventional SMPs, they achieved a soft-to-stiff transition when shape recovered. The stiffening process was driven by water-triggered segmental rearrangement due to the incompatibility between the hard segments and soft PEG segments. Upon hydration, the extent of microphase separation was enhanced and the hard domains were transformed to a more continuous morphology to realize more effective stress transfer. Meanwhile, such segmental rearrangement facilitated the shape recovery process in hydrated state despite the final increased glass transition temperature(Tg ). Our work represents a novel paradigm of simultaneously integrating balanced mechanics, shape memory property and biocompatibility for SMPUs as materials for minimally invasive surgery such as endoluminal stents. This article is protected by copyright. All rights reserved.
    Keywords:  biocompatibility; microphase separation; morphology transformation; shape memory polyurethanes; water-triggered stiffening
  16. Adv Mater. 2022 May 06. e2202992
      Epithelial cell organoids have increased opportunities to probe questions on tissue development and disease in vitro and for therapeutic cell transplantation. Despite their potential, current protocols to grow these organoids almost exclusively depend on culture within three-dimensional (3D) Matrigel, which limits defined culture conditions, introduces animal components, and results in heterogenous organoids (i.e., shape, size, composition). Here, we describe a method that relies on polymeric hydrogel substrates for the generation and expansion of lung alveolar organoids (alveolospheres). Using synthetic hydrogels with defined chemical and physical properties, human induced pluripotent stem cell (iPSC)-derived alveolar type 2 cells (iAT2s) self-assemble into alveolospheres and propagate in Matrigel-free conditions. By engineering pre-defined microcavities within these hydrogels, the heterogeneity of alveolosphere size and structure is reduced when compared to 3D culture, while maintaining alveolar type 2 cell fate of human iAT2-derived progenitor cells. This hydrogel system is a facile and accessible culture system for the culture of iPSC-derived lung progenitors and the method can be expanded to the culture of primary mouse tissue-derived AT2 and other epithelial progenitor and stem cell aggregates. This article is protected by copyright. All rights reserved.
    Keywords:  biomaterials; hyaluronic acid; hydrogels; lung; organoids
  17. Nano Lett. 2022 May 06.
      Spraying serves as an attractive, minimally invasive means of administering hydrogels for localized delivery, particularly due to high-throughput deposition of therapeutic depots over an entire target site of uneven surfaces. However, it remains a great challenge to design systems capable of rapid gelation after shear-thinning during spraying and adhering to coated tissues in wet, physiological environments. We report here on the use of a collagen-binding peptide to enable a supramolecular design of a biocompatible, bioadhesive, and sprayable hydrogel for sustained release of therapeutics. After spraying, the designed peptide amphiphile-based supramolecular filaments exhibit fast, physical cross-linking under physiological conditions. Our ex vivo studies suggest that the hydrogelator strongly adheres to the wet surfaces of multiple organs, and the extent of binding to collagen influences release kinetics from the gel. We envision that the sprayable organ-adhesive hydrogel can serve to enhance the efficacy of incorporated therapeutics for many biomedical applications.
    Keywords:  drug delivery; hydrogels; molecular assembly; peptide amphiphiles; sprayable materials; supramolecular filaments
  18. Adv Sci (Weinh). 2022 May 04. e2105947
      DNA nanomachines with artificial intelligence have attracted great interest, which may open a new era of precision medicine. However, their in vivo behavior, including early diagnosis and therapeutic effect are limited by their targeting efficiency. Here, a tetrahedral DNA framework (TDF)-based nanodevice for in vivo near-infrared (NIR) diagnosis of early-stage AKI is developed. This nanodevice comprises three functional modules: a size-tunable TDF nanostructure as kidney-targeting vehicle, a binding module for the biomarker kidney injury molecule-1 (Kim-1), and a NIR signaling module. The cooperation of these modules allows the nanodevice to be selectively accumulated in injured kidney tissues with high Kim-1 level, generating strong NIR fluorescence; whereas the nanodevice with the proper size can be rapidly cleared in healthy kidneys to minimize the background. By using this nanodevice, the early diagnosis of AKI onset is demonstrated at least 6 h ahead of Kim-1 urinalysis, or 12 h ahead of blood detection. It is envisioned that this TDF-based nanodevice may have implications for the early diagnosis of AKI and other kidney diseases.
    Keywords:  DNA nanodevice; acute kidney injury; early diagnosis; kidney injury molecule-1; tetrahedral DNA framework
  19. ACS Nano. 2022 May 04.
      Many aspects of innate immune responses to SARS viruses remain unclear. Of particular interest is the role of emerging neutralizing antibodies against the receptor-binding domain (RBD) of SARS-CoV-2 in complement activation and opsonization. To overcome challenges with purified virions, here we introduce "pseudovirus-like" nanoparticles with ∼70 copies of functional recombinant RBD to map complement responses. Nanoparticles fix complement in an RBD-dependent manner in sera of all vaccinated, convalescent, and naı̈ve donors, but vaccinated and convalescent donors with the highest levels of anti-RBD antibodies show significantly higher IgG binding and higher deposition of the third complement protein (C3). The opsonization via anti-RBD antibodies is not an efficient process: on average, each bound antibody promotes binding of less than one C3 molecule. C3 deposition is exclusively through the alternative pathway. C3 molecules bind to protein deposits, but not IgG, on the nanoparticle surface. Lastly, "pseudovirus-like" nanoparticles promote complement-dependent uptake by granulocytes and monocytes in the blood of vaccinated donors with high anti-RBD titers. Using nanoparticles displaying SARS-CoV-2 proteins, we demonstrate subject-dependent differences in complement opsonization and immune recognition.
    Keywords:  SARS-CoV-2; antibody; complement; iron oxide nanoparticle; opsonization; receptor-binding domain
  20. Adv Mater. 2022 May 02. e2200549
      Heparins are widely used anticoagulants for surgical procedures and extracorporeal therapies. However, all of them have bleeding risks. Protamine sulfate, the only clinically approved antidote for unfractionated heparin (UFH), has adverse effects. Moreover, protamine can only partially neutralize low-molecular-weight heparins (LMWHs) and is not effective for fondaparinux. Here, an inclusion-sequestration strategy for efficient neutralization of heparin anticoagulants by cationic porous supramolecular organic frameworks (SOFs) and porous organic polymers (POPs) is reported. Isothermal titration calorimetric and fluorescence experiments show strong binding affinities of these porous polymers toward heparins, whereas dynamic light scattering and zeta potential analysis confirm that the heparin sequences are adsorbed into the interior of the porous hosts. Activated partial thromboplastin time, anti-FXa, and thromboelastography assays indicate that their neutralization efficacies are higher than or as high as that of protamine for UFH and generally superior to protamine for LMWHs and fondaparinux, which is further confirmed by tail-transection model in mice and ex vivo aPTT or anti-FXa analysis in rats. Acute toxicity evaluations reveal that one of the SOFs displays outstanding biocompatibility. This work suggests that porous polymers can supply safe and rapid reversal of clinically used heparins, as protamine surrogates, providing an improved approach for their neutralization.
    Keywords:  antidotes; heparin anticoagulants; inclusion-based neutralization; porous organic polymers; supramolecular organic frameworks
  21. ACS Nano. 2022 May 04.
      Titanium dental implants are a multibillion dollar market in the United States alone. The growth of a bacterial biofilm on a dental implant can cause gingivitis, implant loss, and expensive subsequent care. Herein, we demonstrate the efficient eradication of dental biofilm on titanium dental implants via swarming magnetic microrobots based on ferromagnetic (Fe3O4) and photoactive (BiVO4) materials through polyethylenimine micelles. The ferromagnetic component serves as a propulsion force using a transversal rotating magnetic field while BiVO4 is the photoactive generator of reactive oxygen species to eradicate the biofilm colonies. Such photoactive magnetically powered, precisely navigated microrobots are able to destroy biofilm colonies on titanium implants, demonstrating their use in precision medicine.
    Keywords:  bacterial biofilm; ferromagnetic material; micromotors; photoactive material; polymer micelles
  22. ACS Biomater Sci Eng. 2022 May 06.
      Despite advances in laparoscopic surgery combined with neoadjuvant and adjuvant therapy, colon cancer management remains challenging in oncology. Recurrence of cancerous tissue locally or in distant organs (metastasis) is the major problem in colon cancer management. Vaccines and immunotherapies hold promise in preventing cancer recurrence through stimulation of the immune system. We and others have shown that nanoparticles from plant viruses, such as cowpea mosaic virus (CPMV) nanoparticles, are potent immune adjuvants for cancer vaccines and serve as immunostimulatory agents in the treatment or prevention of tumors. While being noninfectious toward mammals, CPMV activates the innate immune system through recognition by pattern recognition receptors (PRRs). While the particulate structure of CPMV is essential for prominent immune activation, the proteinaceous architecture makes CPMV subject to degradation in vivo; thus, CPMV immunotherapy requires repeated injections for optimal outcome. Frequent intraperitoneal (IP) injections however are not optimal from a clinical point of view and can worsen the patient's quality of life due to the hospitalization required for IP administration. To overcome the need for repeated IP injections, we loaded CPMV nanoparticles in injectable chitosan/glycerophosphate (GP) hydrogel formulations, characterized their slow-release potential, and assessed the antitumor preventative efficacy of CPMV-in-hydrogel single dose versus soluble CPMV (single and prime-boost administration). Using fluorescently labeled CPMV-in-hydrogel formulations, in vivo release data indicated that single IP injection of the hydrogel formulation yielded a gel depot that supplied intact CPMV over the study period of 3 weeks, while soluble CPMV lasted only for one week. IP administration of the CPMV-in-hydrogel formulation boosted with soluble CPMV for combined immediate and sustained immune activation significantly inhibited colon cancer growth after CT26 IP challenge in BALB/c mice. The observed antitumor efficacy suggests that CPMV can be formulated in a chitosan/GP hydrogel to achieve prolonged immunostimulatory effects as single-dose immunotherapy against colon cancer recurrence. The present findings illustrate the potential of injectable hydrogel technology to accommodate plant virus nanoparticles to boost the translational development of effective antitumor immunotherapies.
    Keywords:  antitumor immunotherapy; chitosan; colon cancer recurrence; cowpea mosaic virus; in situ forming depot; plant virus; thermosensitive hydrogels
  23. Nat Commun. 2022 May 06. 13(1): 2517
      Colonisation of humans by Staphylococcus aureus is a major risk factor for infection, yet the bacterial and host factors involved are not fully understood. The first step during skin colonisation is adhesion of the bacteria to corneocytes in the stratum corneum where the cornified envelope protein loricrin is the main ligand for S. aureus. Here we report a novel loricrin-binding protein of S. aureus, the cell wall-anchored fibronectin binding protein B (FnBPB). Single-molecule force spectroscopy revealed both weak and ultra-strong (2 nN) binding of FnBPB to loricrin and that mechanical stress enhanced the strength of these bonds. Treatment with a peptide derived from fibrinogen decreased the frequency of strong interactions, suggesting that both ligands bind to overlapping sites within FnBPB. Finally, we show that FnBPB promotes adhesion to human corneocytes by binding strongly to loricrin, highlighting the relevance of this interaction to skin colonisation.
  24. Adv Mater. 2022 May 04. e2201843
      Spider dragline silk is drawn spun from soluble, β-sheet-crosslinked spidroin in aqueous solution. This spider silk has an excellent combination of strength and toughness, which originates from the hierarchical structure containing β-sheet crosslinking points, spiral nanoassemblies, a rigid sheath, and a soft core. Inspired by the spidroin structure and spider spinning process, we prepared a soluble and crosslinked nanogel and drew spun crosslinked fibers with spider-silk-like hierarchical structures containing cross-links, aligned nanoassemblies, and sheath-core structures. Introducing nucleation seeds in the nanogel solution, and applying pre-stretch and spiral architecture in the nanogel fiber, further tuned the alignment and assembly of the polymer chains, and enhanced the breaking strength (1.27 GPa) and toughness (383 MJ m-3 ) to approach those of the best dragline silk. Theoretical modeling provided understanding for the dependence of the fiber's spinning capacity on the nanogel size. This work provides a new strategy for the direct spinning of tough fiber materials. This article is protected by copyright. All rights reserved.
    Keywords:  biomimetic; carbon nanotube; cross-linking; functional fibers; nanomaterials; polymer composite; self-assembly; spinning; strong and tough fibers
  25. Adv Healthc Mater. 2022 May 06. e2200641
      Clinically, bacteria-induced contagion and insufficient osseointegrative property inevitably elicit the failure of orthopedic implants. Herein, a heterostructured coating consisted of simvastatin (SIM)-laden metal-organic frameworks (MOF) and polydopamine (pDA) nanolayers was created on a porous bioinert polyetheretherketone (PEEK) implant. The heteostructured coating significantly promotes cytocompability and osteogenic differentiation through multimodal osteogenicity mechanisms of zinc ion (Zn2+ ) therapy, SIM drug therapy and surface micro-/nano-topological stimulation. Under the illumination of near-infrared (NIR) light, singlet oxygen (1 O2 ) and local hyperthermia are produced; besides, NIR light dramatically accelerates the release of Zn2+ ions from heteostructured coatings. Gram-positive and Gram-negative bacteria are effectively eradicated by the synergy of photothermal/photodynamic effects and photo-induced accelerated delivery of Zn2+ ions. The superior osteogenicity and osseointegration, as well as photoswitchable disinfection controlled by NIR light were corroborated via in vivo results. This work highlights the great potential of photo-responsive heterostructured orthopedic implants in treatment of the noninvasive bone reconstruction of bacteria-associated infectious tissues through multimodal phototherapy and photoswitchable ion-therapy. This article is protected by copyright. All rights reserved.
    Keywords:  Polyetheretherketone; antibacterial; metal-organic framework; osteogenicity; phototherapy