Synthetic Ionizable Colloidal Drug Aggregates Enable Endosomal Disruption

Donders, Eric N.; Slaughter, Kai V; Dank, Christian; Ganesh, Ahil N.; Shoichet, Brian K; Lautens, Mark; Shoichet, Molly S.

doi:10.1002/advs.202300311

Cited by 6 publications

(2 citation statements)

References 69 publications

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“…Galectin family proteins (such as Gal8 or Gal9) bind glycans found on the inner leaflet of endosomal membranes which become available upon endosomal rupture ( 61 ). The cell reporter systems encode for fluorescently tagged Galectins that cluster on endosomes where escape has occurred and can then be imaged ( 47 , 62 – 65 ). With this system, endosomal escape of siRNA-LNPs was observed from RAB5-positive compartments which could have been positive or negative for RAB7 ( 18 ).…”

Section: Methods To Detect Endosomal Escapementioning

confidence: 99%

Endosomal escape: A bottleneck for LNP-mediated therapeutics

Chatterjee,

Kon,

Sharma

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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Lipid nanoparticles (LNPs) have recently emerged as a powerful and versatile clinically approved platform for nucleic acid delivery, specifically for mRNA vaccines. A major bottleneck in the field is the release of mRNA-LNPs from the endosomal pathways into the cytosol of cells where they can execute their encoded functions. The data regarding the mechanism of these endosomal escape processes are limited and contradicting. Despite extensive research, there is no consensus regarding the compartment of escape, the cause of the inefficient escape and are currently lacking a robust method to detect the escape. Here, we review the currently known mechanisms of endosomal escape and the available methods to study this process. We critically discuss the limitations and challenges of these methods and the possibilities to overcome these challenges. We propose that the development of currently lacking robust, quantitative high-throughput techniques to study endosomal escape is timely and essential. A better understanding of this process will enable better RNA-LNP designs with improved efficiency to unlock new therapeutic modalities.

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Section: Methods To Detect Endosomal Escapementioning

confidence: 99%

Endosomal escape: A bottleneck for LNP-mediated therapeutics

Chatterjee,

Kon,

Sharma

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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“…to stabilize CDAs. [105][106][107] While most studies have explored CDAs with chemotherapeutics, they may be equally compelling for use with ocular therapeutics.…”

Section: Drug Conjugates As Their Own Delivery Vehiclesmentioning

confidence: 99%

Long‐Acting Ocular Injectables: Are We Looking In The Right Direction?

Dang,

Shoichet

2023

Advanced Science

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The complex anatomy and physiological barriers of the eye make delivering ocular therapeutics challenging. Generally, effective drug delivery to the eye is hindered by rapid clearance and limited drug bioavailability. Biomaterial‐based approaches have emerged to enhance drug delivery to ocular tissues and overcome existing limitations. In this review, some of the most promising long‐acting injectables (LAIs) in ocular drug delivery are explored, focusing on novel design strategies to improve therapeutic outcomes. LAIs are designed to enable sustained therapeutic effects, thereby extending local drug residence time and facilitating controlled and targeted drug delivery. Moreover, LAIs can be engineered to enhance drug targeting and penetration across ocular physiological barriers.

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Acid‐Responsive Polymer Additives Increase RNA Transfection from Lipid Nanoparticles

Cheung,

Fuchs,

Shoichet

2024

Adv Funct Materials

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Lipid nanoparticles (LNPs) are the most clinically advanced RNA delivery technology, but their efficiency is limited by low RNA release after endosome disruption. To improve RNA release, an acid‐responsive polymer is synthesized with which to formulate LNPs for RNA encapsulation and release. Specifically, three acid‐responsive poly(lactic acid)‐block‐poly(carboxybetaine) zwitterionic derivatives are designed and synthesized that are cationic and complexed with RNA at pH 7.4, but are neutral following cleavage at endosomal pH, thereby having lower affinity to RNA. The polymers are formulated into each of the clinically approved Onpattro, Moderna, or Pfizer LNP formulations to produce hybrid polymer‐lipid nanoparticles (PLNPs). With the PLNPs, the IC50 values of multiple small interfering RNAs (siRNAs) decreased up to 5.4‐fold compared to parent LNPs in several cell lines. Moreover, messenger RNA (mRNA) transfection increased up to two fold. The acid‐responsive polymers in PLNPs accounted for the enhanced RNA transfection as this phenomenon is lost with acid‐inert polymers. Confocal microscopy confirmed that cytosolic RNA concentration increased using the acid‐responsive polymers; conversely, uptake and endosomal escape are identical to existing LNPs. This confirmed that enhanced RNA transfection is due to increased RNA dissociation from its carrier. The novel polymer represents a versatile strategy to increase RNA transfection from LNPs.

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Synthetic Ionizable Colloidal Drug Aggregates Enable Endosomal Disruption

Cited by 6 publications

References 69 publications

Endosomal escape: A bottleneck for LNP-mediated therapeutics

Endosomal escape: A bottleneck for LNP-mediated therapeutics

Long‐Acting Ocular Injectables: Are We Looking In The Right Direction?

Acid‐Responsive Polymer Additives Increase RNA Transfection from Lipid Nanoparticles

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