bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2022‒03‒27
sixteen papers selected by
Ceren Kimna
Technical University of Munich

  1. Adv Mater. 2022 Mar 22. e2109984
      Therapeutic mRNA vaccination is an attractive approach to trigger antitumor immunity. However, the mRNA delivery technology for customized tumor vaccine is still limited. Herein, we employed bacteria-derived outer membrane vesicles (OMVs) as an mRNA delivery platform by genetically engineering with surface decoration of RNA binding protein, L7Ae, and lysosomal escape protein, listeriolysin O (OMV-LL). OMV-LL can rapidly adsorb box C/D sequence-labelled mRNA antigens through L7Ae binding (OMV-LL-mRNA) and deliver them into dendritic cells (DCs), following by the cross-presentation via listeriolysin O-mediated endosomal escape. OMV-LL-mRNA significantly inhibited melanoma progression and elicited a 37.5% complete regression in colon cancer model. OMV-LL-mRNA induced a long-term immune memory and protected the mice from tumor challenge after 60 days. In summary, this platform provides a delivery technology distinct from lipid nanoparticles (LNP) for personalized mRNA tumor vaccination, and with a "Plug-and-Display" strategy that enables its versatile application in mRNA vaccines. This article is protected by copyright. All rights reserved.
    Keywords:  RNA binding protein; box C/D; cancer immunotherapy; mRNA vaccine; outer membrane vesicles; rapid display
  2. Nat Commun. 2022 Mar 24. 13(1): 1585
      Rapid advances in synthetic biology are driving the development of genetically engineered microbes as therapeutic agents for a multitude of human diseases, including cancer. The immunosuppressive microenvironment of solid tumors, in particular, creates a favorable niche for systemically administered bacteria to engraft and release therapeutic payloads. However, such payloads can be harmful if released outside the tumor in healthy tissues where the bacteria also engraft in smaller numbers. To address this limitation, we engineer therapeutic bacteria to be controlled by focused ultrasound, a form of energy that can be applied noninvasively to specific anatomical sites such as solid tumors. This control is provided by a temperature-actuated genetic state switch that produces lasting therapeutic output in response to briefly applied focused ultrasound hyperthermia. Using a combination of rational design and high-throughput screening we optimize the switching circuits of engineered cells and connect their activity to the release of immune checkpoint inhibitors. In a clinically relevant cancer model, ultrasound-activated therapeutic microbes successfully turn on in situ and induce a marked suppression of tumor growth. This technology provides a critical tool for the spatiotemporal targeting of potent bacterial therapeutics in a variety of biological and clinical scenarios.
  3. Nat Nanotechnol. 2022 Mar 24.
      Plasma membrane rupture is a promising strategy for drug-resistant cancer treatment, but its application is limited by the low tumour selectivity of membranolytic molecules. Here we report the design of 'proton transistor' nanodetergents that can convert the subtle pH perturbation signals of tumour tissues into sharp transition signals of membranolytic activity for selective cancer therapy. Our top-performing 'proton transistor' nanodetergent, P(C6-Bn20), can achieve a >32-fold change in cytotoxicity with a 0.1 pH input signal. At physiological pH, P(C6-Bn20) self-assembles into neutral nanoparticles with inactive membranolytic blocks shielded by poly(ethylene glycol) shells, exhibiting low toxicity. At tumour acidity, a sharp transition in its protonation state induces a morphological transformation and an activation of the membranolytic blocks, and the cation-π interaction facilitates the insertion of benzyl groups-containing hydrophobic domains into the cell membranes, resulting in potent membranolytic activity. P(C6-Bn20) is well tolerated in mice and shows high anti-tumour efficacy in various mouse tumour models.
  4. Small. 2022 Mar 20. e2107126
      Ischemic stroke is a leading cause of death and disability and remains without effective treatment options. Improved treatment of stroke requires efficient delivery of multimodal therapy to ischemic brain tissue with high specificity. Here, this article reports the development of multifunctional polymeric nanoparticles (NPs) for both stroke treatment and drug delivery. The NPs are synthesized using an reactive oxygen species (ROS)-reactive poly (2,2'-thiodiethylene 3,3'-thiodipropionate) (PTT) polymer and engineered for brain penetration through both thrombin-triggered shrinkability and AMD3100-mediated targeted delivery. It is found that the resulting AMD3100-conjugated, shrinkable PTT NPs, or ASPTT NPs, efficiently accumulate in the ischemic brain tissue after intravenous administration and function as antioxidant agents for effective stroke treatment. This work shows ASPTT NPs are capable of efficient encapsulation and delivery of glyburide to achieve anti-edema and antioxidant combination therapy, resulting in therapeutic benefits significantly greater than those by either the NPs or glyburide alone. Due to their high efficiency in brain penetration and excellent antioxidant bioactivity, ASPTT NPs have the potential to be utilized to deliver various therapeutic agents to the brain for effective stroke treatment.
    Keywords:  anti-edema; antioxidants; blood-brain barrier; shrinkable nanoparticles; stroke
  5. ACS Nano. 2022 Mar 22.
      The development of bacterial vaccines for inducing an immunoresponse against infectious diseases such as osteomyelitis is of great significance and importance. However, the responsiveness of bacterial immunotherapy remains far from being satisfactory, largely due to the erratic antigen epitopes of bacteria. Herein, we report an in situ vaccination strategy for the immunotherapy of bacterial infection based on an osteomyelitis model using a biomimetic nanomedicine named as HMMP, which was constructed by engineering PpIX-encapsulated hollow MnOx with a hybrid membrane exfoliated from both macrophage and tumor cell lines. The as-established HMMP features a burst bacterial antigen release as the in situ vaccine by the augmented sonodynamic treatment and the resultant priming of antigen-presenting cells for the following activations of both cellular and humoral adaptive immunities against bacterial infections. This treatment regimen not only triggers initial bacterial regression in the established osteomyelitis model but also simultaneously generates robust systemic antibacterial immunity against poorly immunogenic secondary osteomyelitis in the contralateral knee and additionally confers long-lasting bacteria-specific immune memory responses to prevent infection relapse. Thus, our study provides a proof of concept of in situ vaccination for the activation of both innate and adaptive antibacterial immune responses, providing an individual-independent bacterial immunotherapy.
    Keywords:  biomimetic nanomedicine; immune activation; in situ vaccination; osteomyelitis; sonodynamic therapy
  6. Adv Mater. 2022 Mar 20. e2201411
      The development of minimally invasive cardiac patches, either as hemostatic dressing or treating myocardial infarction, is of clinical significance but remains a major challenge. Designing such patches often requires simultaneous consideration of several material attributes, including bioabsorption, non-toxicity, matching the mechanic properties of heart tissues, and working efficiently in wet and dynamic environments. Using genetically engineered multi-domain proteins, we report a printed bi-layer proteinaceous hydrogel patch for heart failure treatments. The intrinsic self-healing nature of hydrogel materials physically enables seamless interfacial integration of two disparate hydrogel layers and functionally endows the cardiac patches with the combinatorial advantages of each layer. Leveraging the biocompatibility, structural stability, and tunable drug release properties of the bi-layer hydrogel, we demonstrate promising effects of hemostasis, fibrosis reduction, and heart function recovery on mice with two myocardium damage models. Moreover, this proteinaceous patch is proved biodegradable in vivo without any additive inflammations. In conclusion, our work introduces a promising new type of minimally invasive patch based on genetically modified double-layer protein gel for treating heart-related injuries or diseases. This article is protected by copyright. All rights reserved.
    Keywords:  cardiac patch; genetically modification; protein hydrogel; wound healing
  7. Adv Mater. 2022 Mar 25. e2108788
      Droplet-based miniature reactors have attracted interest in both fundamental studies, for the unique reaction kinetics they enable, and applications in bio-diagnosis and material synthesis. However, the precise and automatic feeding of chemicals, important for the delicate reactions in these miniaturized chemical reactors, either requires complex, high-cost microfluidic devices or lacks the capability to maintain a pinning-free droplet movement. Here, we report the design and synthesis of a new class of liquid crystal (LC)-based open surfaces which enable a controlled chemical release via a programmable LC phase transition without sacrificing the free transport of the droplets. We demonstrate that their intrinsic slipperiness and self-healing properties enable a modularizable assembly of LC surfaces which can be loaded with different chemicals to achieve a wide range of chemical reactions carried out within droplets, including sequential and parallel chemical reactions, crystal growth and polymer synthesis. Finally, we develop an LC-based chemical feeding device that can automatically control the release of chemicals to direct the simultaneous differentiation of human induced pluripotent stem cells (hiPSCs) into endothelial progenitor cells and cardiomyocytes. Overall, our LC surfaces exhibit desirable levels of automation, responsiveness, and controllability for use in miniature droplet carriers and reactors. This article is protected by copyright. All rights reserved.
    Keywords:  liquid crystals;activated release;droplet reactors;lubricated surfaces;stem cells
  8. Acta Biomater. 2022 Mar 21. pii: S1742-7061(22)00171-4. [Epub ahead of print]
      The treatment of chronic Achilles tendonitis (AT) often requires prolonged therapy and invasive therapeutic methods such as surgery or therapeutic endoscopy. To prevent the progression of chronic AT, excessive inflammation must be alleviated at an early stage. Corticosteroids or nonsteroidal anti-inflammatory drugs are generally prescribed to control inflammation; however, the high doses and long therapeutic periods required may lead to serious side effects. Herein, a local injectable poly(organophosphazene) (PPZ) - celecoxib (CXB) nanoparticle (PCNP) hydrogel system with long-term anti-inflammatory effects was developed for the treatment of tendonitis. The amphiphilic structure and thermosensitive mechanical properties of PPZ means that the hydrophobic CXB can be easily incorporated into the hydrophobic core to form PCNP at 4°C. Following the injection of PCNP into the AT, PCNP hydrogel formed at body temperature and induced long-term local anti-inflammatory effects via sustained release of the PCNP. The therapeutic effects of the injectable PCNP system can alleviate excessive inflammation during the early stages of tissue damage and boost tissue regeneration. This study suggests that PCNP has significant potential as a long-term anti-inflammatory agent through sustained nonsteroidal anti-inflammatory drugs (NSAIDs) delivery and tissue regeneration boosting. STATEMENT OF SIGNIFICANCE: : In the treatment of Achilles tendinitis, a long-term anti-inflammatory effect is needed to alleviate excessive inflammation and induce regeneration of the damaged Achilles tendon. Injectable poly(organophosphazene)(PPZ)-celecoxib(CXB) nanoparticles (PCNP) generated a long-term, localized-anti-inflammatory effect in the injected region, which successfully induced the expression of anti-inflammatory cytokines and suppressed pro-inflammatory cytokines, while the PCNPs degraded completely. Accordingly, regeneration of the damaged Achilles tendon was achieved through the long-term anti-inflammatory effect induced by a single PCNP injection. The PCNP system therefore has great potential in long-term NSAIDs delivery for various tissue engineering applications.
  9. Adv Mater. 2022 Mar 22. e2201210
      Stroke results in the formation of a cavity in the infarcted brain tissue. Angiogenesis and neurogenesis are poor in the cavity, preventing brain tissue regeneration for stroke therapy. To regenerate brain tissue in the cavity, we genetically engineered filamentous phages, the human-safe nanofiber-like bacteria-specific viruses, to display many copies of RGD peptide on the sidewalls. The viral nanofibers, electrostatically coated on the biocompatible injectable silk protein microparticles, not only promoted the adhesion, proliferation, and infiltration of neural stem cells (NSCs), but also induced NSCs to differentiate preferentially into neurons in basal medium within 3 days. After the NSC-loaded microparticles were injected into the stroke cavity of rat models, the phage nanofibers on the microparticles stimulated angiogenesis and neurogenesis in the stroke sites within 2 weeks for brain regeneration, leading to functional recovery of limb motor control of rats within 12 weeks. The viral nanofibers also brought about the desired outcomes for stroke therapy, such as reducing inflammatory response, decreasing thickness of astrocytes scars, and increasing neuroblasts response in the subventricular zone. Since virtually any functional peptide can be displayed on the phage by genetic means, the phage nanofibers hold promise as a unique and effective injectable biomaterial for stroke therapy. This article is protected by copyright. All rights reserved.
    Keywords:  angiogenesis; microparticles; neurogenesis; stroke therapy; viruses
  10. Bioconjug Chem. 2022 Mar 21.
      The combination of photothermal therapy and chemical drug therapy shows good prospects in cancer treatment, but there are also some limitations such as low permeability of therapeutic agents and uneven photothermal therapy. Here, we synthesized a walnut-shaped polydopamine (PDA) nanomotor driven by near infrared (NIR) light. The nanomotor was modified by methoxy polyethylene glycol amine (mPEG-NH2) for improving water solubility. PDA-PEG loaded adriamycin through π-π accumulation and hydrogen bonding. The experimental results showed that the PDA nanomotors had good biocompatibility and photothermal effect. Further, the NIR light irradiation and tumor cell microenvironment are conducive to drug release. In addition, under the irradiation of an NIR laser, the asymmetry of walnut-shaped nanoparticles makes the particles obtain the ability of autonomous movement, which can improve the permeability of particles in 3D tumor balls, which can provide support for drug penetration and heat dispersion. This strategy offers potential innovative materials for photothermal/chemotherapy synergistic therapy of tumors.
  11. ACS Sens. 2022 Mar 21.
      MicroRNAs (miRNAs) play a crucial role in regulating gene expression and have been linked to many diseases. Therefore, sensitive and accurate detection of disease-linked miRNAs is vital to the emerging revolution in early diagnosis of diseases. While the detection of miRNAs is a challenge due to their intrinsic properties such as small size, high sequence similarity among miRNAs and low abundance in biological fluids, the majority of miRNA-detection strategies involve either target/signal amplification or involve complex sensing designs. In this study, we have developed and tested a DNA-based fluorescence resonance energy transfer (FRET) sensor that enables ultrasensitive detection of a miRNA biomarker (miRNA-342-3p) expressed by triple-negative breast cancer (TNBC) cells. The sensor shows a relatively low FRET state in the absence of a target but it undergoes continuous FRET transitions between low- and high-FRET states in the presence of the target. The sensor is highly specific, has a detection limit down to low femtomolar (fM) without having to amplify the target, and has a large dynamic range (3 orders of magnitude) extending to 300 000 fM. Using this strategy, we demonstrated that the sensor allows detection of miRNA-342-3p in the miRNA-extracts from cancer cell lines and TNBC patient-derived xenografts. Given the simple-to-design hybridization-based detection, the sensing platform developed here can be used to detect a wide range of miRNAs enabling early diagnosis and screening of other genetic disorders.
    Keywords:  biomarkers; fluorescence resonance energy transfer (FRET); high-confidence; miRNA; single-molecule; triple negative breast cancer (TNBC)
  12. Proc Natl Acad Sci U S A. 2022 04 05. 119(14): e2119093119
      SignificanceUsing SARS-CoV-2 as a relevant case study for infectious disease, we investigate the structure-function relationships that dictate antiviral spherical nucleic acid (SNA) vaccine efficacy. We show that the SNA architecture can be rapidly employed to target COVID-19 through incorporation of the receptor-binding domain, and that the resulting vaccine potently activates human cells in vitro and mice in vivo. Furthermore, when challenged with a lethal viral infection, only mice treated with the SNA vaccine survived. Taken together, this work underscores the importance of rational vaccine design for infectious disease to yield vaccines that elicit more potent immune responses to effectively fight disease.
    Keywords:  antiviral vaccines; infectious disease; rational vaccinology; spherical nucleic acids
  13. Adv Healthc Mater. 2022 Mar 20. e2200299
      Biofilm is the main culprit of refractory infections and seriously threaten to the human health. Here, a smart hydrogel consisted of norspermidine, aminoglycosides and oxidized polysaccharide was prepared via the formation of acid-labile imine linkage to treat P. aeruginosa biofilm infections in several animal models. The increased acidity caused by bacterial infection triggers the release of norspermidine and aminoglycosides covalently bound with the polymer scaffold. The released norspermidine inhibits biofilm formation and virulence production by regulating the quorum sensing of P. aeruginosa, while the aminoglycoside antibiotics effectively kill the released bacteria. The gel thoroughly inhibited biofilm formation on various medical devices and decreased bacteria pathogenicity. It efficiently inhibited implantation-associated biofilm infections and chronic wound infections, and showed great promising to prevent and treat biofilm-induced refractory infection in clinics. This article is protected by copyright. All rights reserved.
    Keywords:  antibacterial; biofilm; on-demand delivery; smart hydrogel; wound healing
  14. Adv Sci (Weinh). 2022 Mar 24. e2105285
      Self-reporting implantable medical devices are the future of cardiovascular healthcare. Cardiovascular complications such as blocked arteries that lead to the majority of heart attacks and strokes are frequently treated with inert metal stents that reopen affected vessels. Stents frequently re-block after deployment due to a wound response called in-stent restenosis (ISR). Herein, an implantable miniaturized sensor and telemetry system are developed that can detect this process, discern the different cell types associated with ISR, distinguish sub plaque components as demonstrated with ex vivo samples, and differentiate blood from blood clot, all on a silicon substrate making it suitable for integration onto a vascular stent. This work shows that microfabricated sensors can provide clinically relevant information in settings closer to physiological conditions than previous work with cultured cells.
    Keywords:  blood clot; cardiovascular disease; restenosis; stent; wireless impedance sensor
  15. Adv Mater. 2022 Mar 22. e2200254
      Nosocomial infections lead to increased hospital readmissions, post-operation complications, and often death. Many of these infections originate from the use of synthetic materials in the body to which proteins and microorganisms anchor. Unlike growth on tissue, the microbes can grow freely on implantable devices with minimal immune system intervention and often form resilient biofilms that continuously pump out pathogenic cells. The efficacy of antibiotics used to treat infection is declining due to increased rates of pathogenic resistance. We have developed a simple, one-step zwitterionic surface modification to significantly reduce protein and microbial adhesion to synthetic materials and demonstrate the successful modification of several clinically relevant materials, including recalcitrant materials such as elastomeric polydimethylsiloxane (PDMS). The treated surfaces exhibit robust adhesion resistance against proteins and microorganisms in both static and flow conditions. Furthermore, the surface treatment completely prevents the adhesion of mammalian fibroblast cells while displaying no cytotoxicity. To demonstrate the clinical efficacy of the novel technology in the real-world, we have developed a surface-treated, commercial silicone foley catheter that was cleared for use by the U.S. Food and Drug Administration (K192034). 16 long-term catheterized patients received surface-treated catheters and completed a Patient Global Impression of Improvement (PGI-I) questionnaire. 10 out of 16 patients described their urinary tract condition post-implantation as "much better" or "very much better" and 72% (n = 13) of patients desired to continue using the surface-treated catheter over conventional latex or silicone catheters. We propose that this universal, readily scalable antibiofouling surface treatment will improve the safety of implantable devices by reducing patient complications, morbidity, and mortality in hospitals . This article is protected by copyright. All rights reserved.
    Keywords:  antibiofouling; antimicrobial stewardship; crosslinkable coating modification; protein repellant; universal surface treatment; zwitterionic surfaces
  16. Proc Natl Acad Sci U S A. 2022 Mar 29. 119(13): e2115276119
      SignificanceThe treatment of hypoxemia that is refractory to the current standard of care is time-sensitive and requires skilled caregivers and use of specialized equipment (e.g., extracorporeal membrane oxygenation). Most patients experiencing refractory hypoxemia will suffer organ dysfunction, and death is common in this cohort. Here, we describe a new strategy to stabilize and support patients using a microfluidic device that administers oxygen gas directly to the bloodstream in real time and on demand using a process that we call sequential shear-induced bubble breakup. If successful, the described technology may help to avoid or decrease the incidence of ventilator-related lung injury from refractory hypoxemia.
    Keywords:  hypoxia; intravenous; nanobubbles; nanospray; oxygen