bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2022‒03‒06
ten papers selected by
Ceren Kimna
Technical University of Munich

  1. Angew Chem Int Ed Engl. 2022 Feb 28.
      Multivalent interactions of biomolecules play pivotal roles in physiological and pathological settings. Whereas the directionality of the interactions is crucial, the state-of-the-art synthetic multivalent ligand-receptor systems generally lack programmable approaches for orthogonal directionality. Here, we report the design of programmable atom-like nanoparticles (aptPANs) to direct multivalent aptamer-receptor binding on the cell interface. The positions of the aptamer motifs can be prescribed on tetrahedral DNA frameworks to realize atom-like orthogonal valence and direction, enabling the construction of multivalent molecules with fixed aptamer copy numbers but different directionality. These directional-yet-flexible aptPAN molecules exhibit the adaptability to the receptor distribution on cell surfaces. We demonstrate the high-affinity tumor cell binding with a linear aptPAN oligomer (~13-fold improved compared to free aptamers), which leads to ~50% suppression of cell growth.
    Keywords:  DNA frameworks; atom-like nanoparticles; multivalent cell aptamers; stereoisomers
  2. Nano Lett. 2022 Feb 28.
      Atopic dermatitis (AD) is a chronic inflammatory disease associated with unbalanced immune responses in skin tissue. Although steroid drugs and antihistamines are generally used to treat AD, continuous administration causes multiple side effects. High oxidative stress derived from reactive oxygen species (ROS) has been implicated in the pathogenesis of AD. A high level of ROS promotes the release of pro-inflammatory cytokines and T-cell differentiation, resulting in the onset and deterioration of AD. Here, we report a therapeutic hydrogel patch suppressing the high oxidative stress generated in AD lesions. The hydrogel embedded with ROS-scavenging ceria nanoparticles leads to the decrease of both extracellular and intracellular ROS and exhibits cytoprotective effects in a highly oxidative condition. AD-induced mouse model studies show enhanced therapeutic outcomes, including a decrease in the epidermal thickness and levels of AD-associated immunological biomarkers. These findings indicate that a ROS-scavenging hydrogel could be a promising therapeutic hydrogel patch for treating and managing AD.
    Keywords:  atopic dermatitis; ceria nanoparticles; hydrogel patches; inflammatory skin diseases; reactive oxygen species
  3. J Control Release. 2022 Feb 27. pii: S0168-3659(22)00104-3. [Epub ahead of print]
      RGD motif has long been exploited as a versatile tool for targeted drug delivery. However, there are so far no successful clinical translations of RGD functionalized nanomedicines. The lack of comprehensive understanding of their in vivo delivery process poses one of the main obstacles. As a reflection on cRGD-enabled targeting delivery, herein the in vivo fate of cyclic RGD peptide functionalized liposome (cRGD-sLip) and its fundamental mechanism are investigated. cRGD-sLip demonstrates incredibly rapid blood clearance and massive mononuclear phagocytic system (MPS) accumulation after intravenous injection. Phagocytes actively capture cRGD-sLip by recognizing αvβ3 integrins and scavenger receptors, urging reinterrogation of RGD enabled targeting delivery. Intracellular infection with microbes invading and persisting in the phagocytic system poses serious threats to global public health. Most antimicrobial agents are unable to penetrate through host cell membrane and achieve optimal intracellular therapeutic concentration, resulting in ineffective bacterial killing. By leveraging the rapid phagocytic uptake, cRGD-sLip demonstrates the capability to facilitate effective targeted drug delivery to bacteria infected macrophages and successfully reduce the bacterial burden in a murine intracellular Methicillin-resistant Staphylococcus aureus (MRSA) infection model, verifying the potential value of cRGD-sLip in improving therapeutic efficacy of existing antibiotics in the treatment of intracellular bacterial infection.
    Keywords:  Intracellular bacterial infection; Liposome; Methicillin-resistant Staphylococcus aureus (MRSA); RGD; Rapid phagocyte recognition
  4. Nanoscale. 2022 Mar 01.
      The nanoparticle (NP) surfactants generated in situ by binding NPs and polymers can assemble into an elastic NP monolayer at the interface of two immiscible liquids, structuring the liquids. Janus NPs can be more strongly bound to the interface than the NP surfactants, but they are unable to structure liquids into complex shapes due to the difficulty of assembling the jamming arrays. By molecular dynamics simulations, we give an insight into the better performance of NP surfactants than Janus NPs on dynamically structuring liquids. The high energy binding of Janus NPs to the interface will drive the Janus NPs to assemble into micelles in binary liquids. The micelles are stabilized in one liquid by encapsulating a little of the other liquid, hindering interfacial adsorption when the interface is marginally extended upon liquid deformation. In contrast, the in situ formed NP surfactants can rapidly fill the enlarged interfacial area to arrest the consecutive shape changes of the liquids. Moreover, NP surfactants can be designed with an appropriate coverage ratio (≤50%) of NP surface bearing host-guest sites to avoid dissolution and impart a desirable mechanical elasticity to their assembly.
  5. J Am Chem Soc. 2022 Mar 02.
      Biological nanomachines, including proteins and nucleic acids whose function is activated by conformational changes, are involved in every biological process, in which their dynamic and responsive behaviors are controlled by supramolecular recognition. The development of artificial nanomachines that mimic the biological functions for potential application as therapeutics is emerging; however, it is still limited to the lower hierarchical level of the molecular components. In this work, we report a synthetic machinery nanostructure in which actuatable molecular components are integrated into a hierarchical nanomaterial in response to external stimuli to regulate biological functions. Two nanometers core-sized gold nanoparticles are covered with ligand layers as actuatable components, whose folding/unfolding motional response to the cellular environment enables the direct penetration of the nanoparticles across the cellular membrane to disrupt intracellular organelles. Furthermore, the pH-responsive conformational movements of the molecular components can induce the apoptosis of cancer cells. This strategy based on the mechanical motion of molecular components on a hierarchical nanocluster would be useful to design biomimetic nanotoxins.
  6. Anal Chem. 2022 Mar 01.
      Monitoring tumor biomarkers is crucial for cancer diagnosis, progression monitoring, and treatment. However, identifying single or multiple biomarkers with the same spatial locations can cause false-positive feedback. Herein, we integrated the DNA tetrahedron (DT) structures with logic-responsive and signal amplifying capability to construct transmembrane DNA logic nanodevices (TDLNs) for the in situ sequential imaging of transmembrane glycoprotein mucin 1 (MUC1) and cytoplasmic microRNA-21 (miR-21) to cell identifications. The TDLNs were developed by encoding two metastable hairpin DNAs (namely, H1 and H2) in a DT scaffold, in which the triggering toeholds of H1 for miR-21 were sealed by the MUC1-specific aptamer (MUC1-apt). The TDLNs not only had the function of signal amplification owing to the localized catalytic hairpin assembly (CHA) reaction through spatial constraints effect of DT structures but also performed an AND logic operation to output a green Cy3 signal in MCF-7 cells, where MUC1 protein and miR-21 were simultaneously expressed. These results showed that the newly developed TDLNs have better molecular targeting and recognition ability so as to be easily identify cell types and diagnose cancer early.
  7. Adv Mater. 2022 Mar 02. e2110660
      Atherosclerosis (AS) is considered one of the primary causes of cardiovascular diseases (CVDs). Unpredictable rupture of vulnerable atherosclerotic plaques triggers adverse cardiovascular events such as acute myocardial syndrome (ACS) and even sudden cardiac death (SCD). Therefore, assessing the vulnerability of atherosclerotic plaques and early intervention are of significant in reducing CVD mortality. Nanomedicine possesses tremendous advantages in achieving the integration of the diagnosis and therapy of atherosclerotic plaques because of its magnetic, optical, thermal, and catalytic properties. Based on the pathological characteristics of vulnerable plaques, stimuli-responsive nanoplatforms and surface-functionalized nanoagents have been designed and drawn great attention for accomplishing the precise imaging and treatment of vulnerable atherosclerotic plaques due to their superior properties, such as high bioavailability, lesion-targeting specificity, on-demand cargo release, and low off-target damage. Here, we generalize the characteristics of vulnerable plaques, and systematically summarized some targeted strategies for boosting the accuracy of plaque vulnerability evaluation by imaging and the efficacy of plaque stabilization therapy (including antioxidant therapy, macrophage depletion therapy, regulation of lipid metabolism therapy, anti-inflammation therapy, etc.). In addition, we discuss existing challenges and prospects in this field, and believe it will provide new thinking for the diagnosis and treatment of CVDs in the near future. This article is protected by copyright. All rights reserved.
    Keywords:  atherosclerosis; imaging; nanomedicine; targeted therapy; vulnerable plaque
  8. Sci Adv. 2022 Mar 04. 8(9): eabm3378
      Interrelated coagulation and inflammation are impediments to endothelialization, a prerequisite for the long-term function of cardiovascular materials. Here, we proposed a self-regulating anticoagulant coating strategy combined with anti-inflammatory capacity, which consisted of thrombin-responsive nanogels with anticoagulant and anti-inflammatory components. As an anticoagulant, rivaroxaban was encapsulated in nanogels cross-linked by thrombin-cleavable peptide and released upon the trigger of environmental thrombin, blocking the further coagulation cascade. The superoxide dismutase mimetic Tempol imparted the antioxidant property. Polyphenol epigallocatechin gallate (EGCG), in addition to its anti-inflammatory function in synergy with Tempol, also acted as a weak cross-linker to stabilize the coating. The effectiveness and versatility of this coating were validated using two typical cardiovascular devices as models, biological valves and vascular stents. It was demonstrated that the coating worked as a precise strategy to resist coagulation and inflammation, escorted reendothelialization on the cardiovascular devices, and provided a new perspective for designing endothelium-like functional coatings.
  9. Oncogene. 2022 Feb 26.
      The small arginine-rich protein protamine condenses complete genomic DNA into the sperm head. Here, we applied its high RNA binding capacity for spontaneous electrostatic assembly of therapeutic nanoparticles decorated with tumour-cell-specific antibodies for efficiently targeting siRNA. Fluorescence microscopy and DLS measurements of these nanocarriers revealed the formation of a vesicular architecture that requires presence of antibody-protamine, defined excess of free SMCC-protamine, and anionic siRNA to form. Only these complex nanoparticles were efficient in the treatment of non-small-cell lung cancer (NSCLC) xenograft models, when the oncogene KRAS was targeted via EGFR-mediated delivery. To show general applicability, we used the modular platform for IGF1R-positive Ewing sarcomas. Anti-IGR1R-antibodies were integrated into an antibody-protamine nanoparticle with an siRNA specifically against the oncogenic translocation product EWS/FLI1. Using these nanoparticles, EWS/FLI1 knockdown blocked in vitro and in vivo growth of Ewing sarcoma cells. We conclude that these antibody-protamine-siRNA nanocarriers provide a novel platform technology to specifically target different cell types and yet undruggable targets in cancer therapy by RNAi.
  10. Adv Mater. 2022 Mar 03. e2201326
      Living biological systems, ranging from single cells to whole organisms, can sense, process information, and actuate in response to changing environmental conditions. Inspired by living biological systems, engineered living cells and non-living matrices are brought together, which gives rise to the technology of engineered living materials. By designing the functionalities of living cells and the structures of non-living matrices, engineered living materials can be created to detect variability in the surrounding environment and to adjust their functions accordingly, thereby enabling applications in health monitoring, disease treatment, and environmental remediation. Hydrogels, a class of soft, wet, and biocompatible materials, have been widely used as matrices for engineered living cells, leading to the nascent field of engineered living hydrogels. Here, we discuss the interactions between hydrogel matrices and engineered living cells, focusing on how hydrogels influence cell behaviours and how cells affect hydrogel properties. We also discuss the interactions between engineered living hydrogels and their environments, and how these interactions enable versatile applications. Finally, we highlight current challenges facing the field of engineered living hydrogels for their applications in clinical and environmental settings. This article is protected by copyright. All rights reserved.
    Keywords:  engineered living hydrogels; microbe-material interaction; real-world applications; synthetic biology