A molecular sensor to quantify the localization of proteins, DNA and nanoparticles in cells

FitzGerald, Laura I.; Aurelio, Luigi; Chen, Moore; Yuen, Daniel; Rennick, Joshua J.; Graham, Bim; Johnston, Angus P. R.

doi:10.1038/s41467-020-18082-8

Cited by 28 publications

(25 citation statements)

References 58 publications

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“…3D CLSM showed that NR@FAM NPs bound with MRSA in stereo space vision (Figure 4B), further confirming intracellular MRSA targeting of NR@FAM NPs. [ 28 ] In contrast, NR@FM NPs evenly distributed around the nuclei of THP‐1 cells, regardless of the locations of intracellular MRSA. 3D renderings clearly showed that the fluorescence signals between NR@FM NPs and MRSA did not overlap (Figure 4B).…”

Section: Resultsmentioning

confidence: 99%

Cascade‐Targeting Poly(amino acid) Nanoparticles Eliminate Intracellular Bacteria via On‐Site Antibiotic Delivery

Feng

Kang

et al. 2022

Advanced Materials

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serious infections including tuberculosis, endocarditis, osteomyelitis, necrotizing pneumonia, and sepsis. [1] Treatment often requires long-term and intensive antibiotics administration; however, treatment failure and relapse are unfortunately common. [2] As we currently understand it, the major reasons for the failure of clinical therapy to eradicate intracellular bacteria include: i) poor cellular membrane penetration, suboptimal intracellular accumulation, and short retention of antibiotics; [3] ii) diminished antibacterial activity of antibiotics because of the harsh acidic and hydrolytic environment within phagolysosomes; [4] iii) intracellular bacteria being in a dormant state and tolerance of otherwise lethal concentration of antibiotics; [5] and iv) bacteria escape from phagolysosomes and hide in privileged intracellular compartments that evade the bactericidal actions of antibiotics. [6] At later timepoints, potentially after the cessation of therapy, the bacteria may then proliferate resulting in the apoptosis and autophagy of the cells. The evasive bacteria re-enter the circulation or re-infect local tissues. [7] As such, the infected cells have been likened to "Trojan horses" that protect bacteria with later dissemination of the infection into deeper tissues. [8] Drug delivery systems (DDSs) have shown increasing potential for the treatment of intracellular bacterial infection. [9] The Intracellular bacteria in latent or dormant states tolerate high-dose antibiotics. Fighting against these opportunistic bacteria has been a long-standing challenge. Herein, the design of a cascade-targeting drug delivery system (DDS) that can sequentially target macrophages and intracellular bacteria, exhibiting on-site drug delivery, is reported. The DDS is fabricated by encapsulating rifampicin (Rif ) into mannose-decorated poly(α-N-acryloylphenylalanine)-block-poly(β-N-acryloyl-d-aminoalanine) nanoparticles, denoted as Rif@FAM NPs. The mannose units on Rif@FAM NPs guide the initial macrophage-specific uptake and intracellular accumulation. After the uptake, the detachment of mannose in acidic phagolysosome via Schiff base cleavage exposes the d-aminoalanine moieties, which subsequently steer the NPs to escape from lysosomes and target intracellular bacteria through peptidoglycan-specific binding, as evidenced by the in situ/ex situ co-localization using confocal, flow cytometry, and transmission electron microscopy. Through the on-site Rif delivery, Rif@FAM NPs show superior in vitro and in vivo elimination efficiency than the control groups of free Rif or the DDSs lacking the macrophages-or bacteria-targeting moieties. Furthermore, Rif@FAM NPs remodel the innate immune response of the infected macrophages by upregulating M1/M2 polarization, resulting in a reinforced antibacterial capacity. Therefore, this biocompatible DDS enabling macrophages and bacteria targeting in a cascade manner provides a new outlook for the therapy of intracellular pathogen infection.

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Section: Resultsmentioning

confidence: 99%

Cascade‐Targeting Poly(amino acid) Nanoparticles Eliminate Intracellular Bacteria via On‐Site Antibiotic Delivery

Feng

Kang

et al. 2022

Advanced Materials

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“…However, these endpoint measurements are dependent on downstream processing after endosomal escape occurs. Recent advances in endosomal escape assays are helping to understand cytosolic delivery [ 44 , 45 ]. These cellular assays can be combined with liposomal leakage assays which can be used to probe the membrane disruption potential of different LNP formulations [ 46 ].…”

Section: Improving Cytosolic Deliverymentioning

confidence: 99%

Opportunities for innovation: Building on the success of lipid nanoparticle vaccines

Huang

Yuen

Mintern

et al. 2021

Current Opinion in Colloid & Interface Science

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Lipid nanoparticle (LNP) formulations of messenger RNA (mRNA) have demonstrated high efficacy as vaccines against SARS-CoV-2. The success of these nanoformulations underscores the potential of LNPs as delivery system for next generation biological therapies. In this article, we highlight the key considerations necessary for engineering LNPs as a vaccine delivery system and explore areas for further optimisation. There remain opportunities to improve protection of mRNA, optimise cytosolic delivery, target specific cells, minimise adverse side effects and control release of RNA from the particle. The modular nature of LNP formulations and the flexibility of mRNA as a payload provide many pathways to implement these strategies. Innovation in LNP vaccines is likely to accelerate with increased enthusiasm following recent successes, however any advances will have implications for a broad range of therapeutic applications beyond vaccination such as gene therapy.

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“…Therefore, there is a need for further understanding of intracellular trafficking after endocytosis, as especially for siRNA, since its subcellular fate is paramount for it to elucidate a therapeutic effect. [ 49 ]…”

Section: Barriers To Overcomementioning

confidence: 99%

Overcoming Barriers: Clinical Translation of siRNA Nanomedicines

Tieu

Wei

Cifuentes‐Rius

et al. 2021

Advanced Therapeutics

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RNA interference has garnered new hope for many difficult to treat diseases that have been “undruggable” using conventional small molecule drugs or monoclonal antibodies. Small interfering RNA (siRNA) has shown great strides in targeting difficult to treat diseases as siRNA therapeutics are able to efficiently silence specific genes throughout the body. This review highlights major barriers in siRNA delivery and how nanoparticles have been used to circumvent these barriers. The authors outline many of the recent promising preclinical successes in siRNA delivery using nanoparticles. Importantly, the review examines current FDA‐approved siRNA therapeutics and provides a comprehensive analysis of current siRNA candidates in clinical trials. Lastly, the authors discuss future challenges and opportunities in this expansive field of research.

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A molecular sensor to quantify the localization of proteins, DNA and nanoparticles in cells

Cited by 28 publications

References 58 publications

Cascade‐Targeting Poly(amino acid) Nanoparticles Eliminate Intracellular Bacteria via On‐Site Antibiotic Delivery

Cascade‐Targeting Poly(amino acid) Nanoparticles Eliminate Intracellular Bacteria via On‐Site Antibiotic Delivery

Opportunities for innovation: Building on the success of lipid nanoparticle vaccines

Overcoming Barriers: Clinical Translation of siRNA Nanomedicines

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