Therapeutic applications of nanoparticles targeting neutrophil and extracellular traps

Rezaei, Nastaran; Zadory, Matthias; Babity, Samuel; Marleau, Sylvie

doi:10.1016/j.jconrel.2023.05.018

Cited by 4 publications

(2 citation statements)

References 173 publications

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“…NE and PR3) may allow further improvement. [32][33][34][35] Exploiting dysregulated proteases in the diseased microenvironment presents an additional avenue for conditional therapeutic development, provided the optimal combination of VHH target and cleavable linker can be identified.…”

Section: Optimal Therapeutic Effect Of Vhh-targeted Conditional Antim...mentioning

confidence: 99%

Nanobody-targeted conditional antimicrobial therapeutics

Ngambenjawong,

Ko,

Pishesha

et al. 2024

Preprint

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Conditional therapeutics that rely on disease microenvironment-specific triggers for activation are a promising strategy to improve therapeutic cargos. Among the investigated triggers, protease activity is used most often, because of its dysregulation in several diseases. How to optimally fine-tune protease activation for different therapeutic cargos remains a challenge. Here, we designed nanobody-targeted conditional antimicrobial therapeutics to deliver a model therapeutic peptide and protein to the site of bacterial infection. We explored several parameters that influence proteolytic activation. We report the use of targeting nanobodies to enhance the activation of therapeutics that are otherwise activated inefficiently, despite extensive optimization of the cleavable linker. Specifically, pairing of Ly6G/C or ADAM10-targeting nanobodies with ADAM10-cleavable linkers improved activation via proximity-enabled reactivity. More broadly, this optimization framework provides a guideline for the development of conditional therapeutics to treat various diseases where protease activity is dysregulated.

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Section: Optimal Therapeutic Effect Of Vhh-targeted Conditional Antim...mentioning

confidence: 99%

Nanobody-targeted conditional antimicrobial therapeutics

Ngambenjawong,

Ko,

Pishesha

et al. 2024

Preprint

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“…Systemic application of NET-degrading drugs has some drawbacks, such as low specificity, poor efficacy, and severe side effects . Thus, constructing drug delivery systems specifically recognizing NETs is important but still challenged. , Due to NETs’ negative charge, Chen et al and Mao et al proposed different cationic materials, which could passively bind to NETs. , However, electrostatic interaction may lack specificity and effectiveness in vivo.…”

Section: Introductionmentioning

confidence: 99%

A Two-Pronged Delivery Strategy Disrupting Positive Feedback Loop of Neutrophil Extracellular Traps for Metastasis Suppression

Kong,

Deng,

et al. 2024

ACS Nano

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Neutrophil extracellular traps (NETs) severely affect tumor metastasis through a self-perpetuating feedback loop involving two key steps: (1) mitochondrial aerobic respiration-induced hypoxia promotes NET formation and (2) NETs enhance mitochondrial metabolism to exacerbate hypoxia. Herein, we propose a two-pronged approach with the activity of NET-degrading and mitochondrion-damaging by simultaneously targeting drugs to NETs and tumor mitochondria of this loop. In addition to specifically recognizing and eliminating extant NETs, the NET-targeting nanoparticle also reduces NET-induced mitochondrial biogenesis, thus inhibiting the initial step of the feedback loop and mitigating extant NETs' impact on tumor metastasis. Simultaneously, the mitochondrion-targeting system intercepts mitochondrial metabolism and alleviates tumor hypoxia, inhibiting neutrophil infiltration and subsequent NET formation, which reduces the source of NETs and disrupts another step of the self-amplifying feedback loop. Together, the combination significantly reduces the formation of NET− tumor cell clusters by disrupting the interaction between NETs and tumor mitochondria, thereby impeding the metastatic cascade including tumor invasion, hematogenous spread, and distant colonization. This work represents an innovative attempt to disrupt the feedback loop in tumor metastasis, offering a promising therapeutic approach restraining NET-assisted metastasis.

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