bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2022‒06‒19
thirteen papers selected by
Ceren Kimna
Technical University of Munich

  1. Adv Mater. 2022 Jun 15. e2203309
      Immunotherapy has received tremendous attention for tumor treatment, but the efficacy is greatly hindered by insufficient tumor-infiltration of immune cells and immunosuppressive tumor microenvironment. The strategy that can efficiently activate cytotoxic T lymphocytes and inhibit negative immune regulators will greatly amplify immunotherapy outcome, which is however very rare. Herein, we develop a new kind of semiconducting polymer nanoparticles featured with surface-mimicking protein secondary structure (SPSS NPs) for self-synergistic cancer immunotherapy by combining immunogenic cell death (ICD) and immune checkpoint blockade (ICB) therapy. The semiconducting polymers with excellent photodynamic property are synthesized by rational fluorination, which could massively induce ICD. Additionally, the peptide antagonists are introduced and self-assembled into β-sheet protein secondary structures on the photodynamic nanoparticle surface via preparation process optimization, which function as efficient lysosome-targeting chimaeras (LYTACs) to mediate the degradation of PD-L1 in lysosome. In vivo experiments demonstrate that SPSS NPs could not only elicit strong antitumor immunity to suppress the growth of both primary tumor and distant tumor, but also evoke long-term immunological memory against tumor rechallenge. This work introduces a new kind of robust immunotherapy agents by combining well-designed photosensitizer-based ICD induction and protein secondary structures-mediated LYTAC-like multivalence PD-L1 blockade, rendering great promise for synergistic immunotherapy. This article is protected by copyright. All rights reserved.
    Keywords:  aggregation-induced emission photosensitizer; cancer immunotherapy; immunogenic cell death; self-assembling peptide; semiconducting polymer nanoparticle
  2. Adv Healthc Mater. 2022 Jun 16. e2200416
      Thromboembolic stroke is typically characterized by the activation of platelets, resulting in thrombus in the cerebral vascular system, leading to high morbidity and mortality globally. Intravenous thrombolysis by tissue plasminogen activator (tPA) administration within 4.5 h from the onset of symptoms is providing a standard therapeutic strategy for ischemic stroke, but this reagent simultaneously shows potential serious adverse effects, e.g. hemorrhagic transformation. Herein, a novel delivery platform based on Annexin V and platelet membrane was developed for tPA (APLT-PA) to enhance targeting efficiency, therapeutic effects and reduce the risk of intracerebral hemorrhage in acute ischemic stroke. After preparation by extrusion of platelet membrane and subsequent insertion of Annexin V to liposomes, APLT-PA exhibited a high targeting efficiency to activated platelet in vitro and thrombosis site in vivo, due to the binding to phosphatidylserine (PS) and activated platelet membrane proteins. One dose of APLT-PA led to obvious thrombolysis and significant improvement of neurological function within 7 days in mice with photochemically induced acute ischemic stroke. This study provides a novel, safe platelet-biomimetic nanomedicine for precise thrombolytic treatment in acute ischemic stroke, and offers new theories for the design and exploitation of cell-mimetic nanomedicine in diverse biomedical applications. This article is protected by copyright. All rights reserved.
    Keywords:  Acute ischemic stroke; Annexin V; Phosphatidylserine; Platelet biomimetic; Tissue plasminogen activator (tPA)
  3. Nat Commun. 2022 Jun 14. 13(1): 3432
      Reactive oxygen species (ROS) play vital roles in intestinal inflammation. Therefore, eliminating ROS in the inflammatory site by antioxidant enzymes such as catalase and superoxide dismutase may effectively curb inflammatory bowel disease (IBD). Here, Escherichia coli Nissle 1917 (ECN), a kind of oral probiotic, was genetically engineered to overexpress catalase and superoxide dismutase (ECN-pE) for the treatment of intestinal inflammation. To improve the bioavailability of ECN-pE in the gastrointestinal tract, chitosan and sodium alginate, effective biofilms, were used to coat ECN-pE via a layer-by-layer electrostatic self-assembly strategy. In a mouse IBD model induced by different chemical drugs, chitosan/sodium alginate coating ECN-pE (ECN-pE(C/A)2) effectively relieved inflammation and repaired epithelial barriers in the colon. Unexpectedly, such engineered EcN-pE(C/A)2 could also regulate the intestinal microbial communities and improve the abundance of Lachnospiraceae_NK4A136 and Odoribacter in the intestinal flora, which are important microbes to maintain intestinal homeostasis. Thus, this study lays a foundation for the development of living therapeutic proteins using probiotics to treat intestinal-related diseases.
  4. Nat Commun. 2022 Jun 16. 13(1): 3468
      Checkpoint immunotherapies have been combined with other therapeutic modalities to increase patient response rate and improve therapeutic outcome, which however exacerbates immune-related adverse events and requires to be carefully implemented in a narrowed therapeutic window. Strategies for precisely controlled combinational cancer immunotherapy can tackle this issue but remain lacking. We herein report a catalytical nano-immunocomplex for precise and persistent sono-metabolic checkpoint trimodal cancer therapy, whose full activities are only triggered by sono-irradiation in tumor microenvironment (TME). This nano-immunocomplex comprises three FDA-approved components, wherein checkpoint blockade inhibitor (anti-programmed death-ligand 1 antibody), immunometabolic reprogramming enzyme (adenosine deaminase, ADA), and sonosensitizer (hematoporphyrin) are covalently immobilized into one entity via acid-cleavable and singlet oxygen-activatable linkers. Thus, the activities of the nano-immunocomplex are initially silenced, and only under sono-irradiation in the acidic TME, the sonodynamic, checkpoint blockade, and immunometabolic reprogramming activities are remotely awakened. Due to the enzymatic conversion of adenosine to inosine by ADA, the nano-immunocomplex can reduce levels of intratumoral adenosine and inhibit A2A/A2B adenosine receptors-adenosinergic signaling, leading to efficient activation of immune effector cells and inhibition of immune suppressor cells in vivo. Thus, this study presents a generic and translatable nanoplatform towards precision combinational cancer immunotherapy.
  5. Adv Funct Mater. 2021 Sep 09. 31(37): 2104843
      The authors aim to develop siRNA therapeutics for cancer that can be administered systemically to target tumors and retard their growth. The efficacy of systemic delivery of siRNA to tumors with nanoparticles based on lipids or polymers is often compromised by their rapid clearance from the circulation by the liver. Here, multifunctional cationic and anionic siRNA nanoparticle formulations are described, termed receptor-targeted nanocomplexes (RTNs), that comprise peptides for siRNA packaging into nanoparticles and receptor-mediated cell uptake, together with lipids that confer nanoparticles with stealth properties to enhance stability in the circulation, and fusogenic properties to enhance endosomal release within the cell. Intravenous administration of RTNs in mice leads to predominant accumulation in xenograft tumors, with very little detected in the liver, lung, or spleen. Although non-targeted RTNs also enter the tumor, cell uptake appears to be RGD peptide-dependent indicating integrin-mediated uptake. RTNs with siRNA against MYCN (a member of the Myc family of transcription factors) in mice with MYCN-amplified neuroblastoma tumors show significant retardation of xenograft tumor growth and enhanced survival. This study shows that RTN formulations can achieve specific tumor-targeting, with minimal clearance by the liver and so enable delivery of tumor-targeted siRNA therapeutics.
    Keywords:  MYCN; neuroblastomas; siRNA; tumors; tumor‐specific delivery
  6. Sci Adv. 2022 Jun 17. 8(24): eabm4389
      Traceless physical cues are desirable for remote control of the in situ production and real-time dosing of biopharmaceuticals in cell-based therapies. However, current optogenetic, magnetogenetic, or electrogenetic devices require sophisticated electronics, complex artificial intelligence-assisted software, and external energy supplies for power and control. Here, we describe a self-sufficient subcutaneous push button-controlled cellular implant powered simply by repeated gentle finger pressure exerted on the overlying skin. Pushing the button causes transient percutaneous deformation of the implant's embedded piezoelectric membrane, which produces sufficient low-voltage energy inside a semi-permeable platinum-coated cell chamber to mediate rapid release of a biopharmaceutical from engineered electro-sensitive human cells. Release is fine-tuned by varying the frequency and duration of finger-pressing stimulation. As proof of concept, we show that finger-pressure activation of the subcutaneous implant can restore normoglycemia in a mouse model of type 1 diabetes. Self-sufficient push-button devices may provide a new level of convenience for patients to control their cell-based therapies.
  7. J Control Release. 2022 Jun 13. pii: S0168-3659(22)00336-4. [Epub ahead of print]348 444-455
      Cancer drug delivery systems often suffer from premature drug leakage during transportation and/or inefficient drug release within cancer cells. We present here a polymeric prodrug nanoassembly that addresses these problems simultaneously. This nanoassembly comprises a polymeric prodrug with novel trivalent phenylboronate moieties for drug conjugation via ether linkages, as well as β-lapachone (Lapa). While the ether linkage enables nearly no drug release under physiological conditions, the Lapa molecules can induce the reactive oxygen species (ROS) burst specifically in cancer cells via NAD(P)H: quinone oxidoreductase-1 catalysis, which triggers the cleavage of the ether bonds and thus cascade amplification drug release in cancer cells. As a result, the nanoassemblies exhibit much higher cytotoxicity against cancer cells than normal cells, and also increased therapeutic efficacy and reduced side effects compared to the clinically used irinotecan. We anticipate that this strategy can be applied to other drug delivery platforms to enable more precise drug release.
    Keywords:  7-ethyl-10-hydroxycamptothecin; Cancer therapy; Cascade amplification drug release; Drug delivery; Linker; Nanoassembly; Reactive oxygen species; β-Lapachone
  8. Cancer Sci. 2022 Jun 14.
      Oligonucleotide therapeutics, drugs consisting of 10-50 nucleotide-long single- or double-stranded DNA or RNA molecules that can bind to specific DNA or RNA sequences or proteins, include antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), microRNAs (miRNAs), aptamers, and decoys. These can potentially become the third pillar of drug development. In particular, ASOs and siRNAs are widely used advanced tools to silence gene expression and are used in clinical trials, as they have high specificity for target mRNAs or non-coding RNAs and limited toxicity. However, their clinical application is still challenging. Although chemotherapy has benefits, it causes severe adverse effects in many patients. Therefore, new modalities for targeted molecular therapy against tumors, including oligonucleotide therapeutics, are required, and they should be compatible with diagnosis using next-generation sequencing. This review provides an overview of the therapeutic uses of ASOs, siRNAs, and miRNAs in clinical studies on malignant tumors. Understanding previous research and development will help develop novel oligonucleotide therapeutics against malignant tumors.
    Keywords:  antisense oligonucleotide; drug delivery; microRNA; oligonucleotide therapeutics; small interfering RNA
  9. Adv Funct Mater. 2022 Jun 10. pii: 2113383. [Epub ahead of print]32(24):
      Corneal injuries are a major cause of blindness worldwide. To restore corneal integrity and clarity, there is a need for regenerative bio-integrating materials for in-situ repair and replacement of corneal tissue. Here, we introduce Light-curable COrnea Matrix (LC-COMatrix), a tunable material derived from decellularized porcine cornea extracellular matrix containing un-denatured collagen and sulfated glycosaminoglycans. It is a functionalized hydrogel with proper swelling behavior, biodegradation, and viscosity that can be cross-linked in situ with visible light, providing significantly enhanced biomechanical strength, stability, and adhesiveness. Cross-linked LC-COMatrix strongly adheres to human corneas ex vivo and effectively closes full-thickness corneal perforations with tissue loss. Likewise, in vivo, LC-COMatrix seals large corneal perforations, replaces partial-corneal stromal defects and bio-integrates into the tissue in rabbit models. LC-COMatrix is a natural ready-to-apply bio-integrating adhesive that is representative of native corneal matrix with potential applications in corneal and ocular surgeries.
    Keywords:  Bio-adhesive; Cornea; Decellularized Tissue; Extracellular Matrix; Hydrogel; Light-Curing
  10. Biomaterials. 2022 Jun 05. pii: S0142-9612(22)00259-9. [Epub ahead of print]287 121619
      Subcutaneous administration of sustained-release formulations is a common strategy for protein drugs, which avoids first pass effect and has high bioavailability. However, conventional sustained-release strategies can only load a limited amount of drug, leading to insufficient durability. Herein, we developed microcapsules based on engineered bacteria for sustained release of protein drugs. Engineered bacteria were carried in microcapsules for subcutaneous administration, with a production-lysis circuit for sustained protein production and release. Administrated in diabetic rats, engineered bacteria microcapsules was observed to smoothly release Exendin-4 for 2 weeks and reduce blood glucose. In another example, by releasing subunit vaccines with bacterial microcomponents as vehicles, engineered bacterial microcapsules activated specific immunity in mice and achieved tumor prevention. The engineered bacteria microcapsules have potential to durably release protein drugs and show versatility on the size of drugs. It might be a promising design strategy for long-acting in situ drug factory.
    Keywords:  Bacterial microcomponents; Hydrogel microcapsules; Optogenetics; Sustained release; Synthetic biology
  11. ACS Nano. 2022 Jun 13.
      Supramolecular nanofunctional materials have attracted increasing attention from scientific researchers due to their advantages in biomedicine. Herein, we construct a nanosupramolecular cascade reactor through the cooperative interaction of multiple noncovalent bonds, which include chitosan, sulfobutylether-β-cyclodextrin, ferrous ions, and glucose oxidase. Under the activation of glucose, hydroxyl radicals generated from the nanoconfinement supramolecular cascade reaction process are able to initiate the radical polymerization process of vinyl monomers to form hydrogel network structures while inhibiting resistant bacterial infection. The results of the diabetic wound experiment confirmed the capacity of the glucose-activated nanoconfinement supramolecular cascade reaction in situ for potent antimicrobial efficacy and wound protection. This strategy of "two birds with one stone" provides a convenient method for the application of supramolecular nanomaterial in the field of biomedicine.
    Keywords:  antibacterial; diabetes chronic wound; hydrogel; sulfobutylether-β-cyclodextrin; supramolecular cascade reactor
  12. Nat Commun. 2022 Jun 14. 13(1): 3430
      CRISPR SWAPnDROP extends the limits of genome editing to large-scale in-vivo DNA transfer between bacterial species. Its modular platform approach facilitates species specific adaptation to confer genome editing in various species. In this study, we show the implementation of the CRISPR SWAPnDROP concept for the model organism Escherichia coli, the fast growing Vibrio natriegens and the plant pathogen Dickeya dadantii. We demonstrate the excision, transfer and integration of large chromosomal regions between E. coli, V. natriegens and D. dadantii without size-limiting intermediate DNA extraction. CRISPR SWAPnDROP also provides common genome editing approaches comprising scarless, marker-free, iterative and parallel insertions and deletions. The modular character facilitates DNA library applications, and recycling of standardized parts. Its multi-color scarless co-selection system significantly improves editing efficiency and provides visual quality controls throughout the assembly and editing process.
  13. ACS Nano. 2022 Jun 17.
      Fabrication of nanoscale DNA devices to generate 3D nano-objects with precise control of shape, size, and presentation of ligands has shown tremendous potential for therapeutic applications. The interactions between the cell membrane and different topologies of 3D DNA nanostructures are crucial for designing efficient tools for interfacing DNA devices with biological systems. The practical applications of these DNA nanocages are still limited in cellular and biological systems owing to the limited understanding of their interaction with the cell membrane and endocytic pathway. The correlation between the geometry of DNA nanostructures and their internalization efficiency remains elusive. We investigated the influence of the shape and size of 3D DNA nanostructures on their cellular internalization efficiency. We found that one particular geometry, i.e., the tetrahedral shape, is more favored over other designed geometries for their cellular uptake in 2D and 3D cell models. This is also replicable for cellular processes like cell invasion assays in a 3D spheroid model, and passing the epithelial barriers in in vivo zebrafish model systems. Our work provides detailed information for the rational design of DNA nanodevices for their upcoming biological and biomedical applications.
    Keywords:  3D spheroid; DNA nanostructure; endocytosis; geometry; in vivo; tetrahedron