PEGylation of poly(amine-co-ester) polyplexes for tunable gene delivery

Grun, Molly K; Suberi, Alexandra; Shin, Kwangsoo; Lee, Teresa; Gomerdinger, Victoria; Moscato, Zoe; Piotrowski-Daspit, Alexandra S.; Saltzman, W. Mark

doi:10.1016/j.biomaterials.2021.120780

Cited by 47 publications

(54 citation statements)

References 40 publications

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“…We next assessed the ability of alternative platforms for IN Spike boosting. Poly(amine-co-ester)s (PACE) are biodegradable terpolymers that have been developed to encapsulate and deliver nucleic acids such as mRNA or DNA to specified tissues in vivo depending on the properties of the polymer ( 31 ). Recent studies have shown that mRNA-LNP delivered to the respiratory tract is lethal in a dose dependent manner in mice ( 32 ).…”

Section: Resultsmentioning

confidence: 99%

“…PACE polymers were dissolved at 100 mg/mL overnight in DMSO (37°C, shaking). Prior to polyplex fabrication, an optimal PACE polymer blend was produced by mixing solutions of PACE polymers containing an end-group modification ( 40 ) and a polyethylene glycol tail ( 31 ). mRNA and polymer were diluted into equal volumes of sodium acetate buffer (25 mM, pH 5.8).…”

Section: Methodsmentioning

confidence: 99%

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Unadjuvanted intranasal spike vaccine booster elicits robust protective mucosal immunity against sarbecoviruses

Mao

Israelow

Suberi

et al. 2022

Preprint

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As the SARS-CoV-2 pandemic enters its third year, vaccines that not only prevent disease, but also prevent transmission are needed to help reduce global disease burden. Currently approved parenteral vaccines induce robust systemic immunity, but poor immunity at the respiratory mucosa. Here we describe the development of a novel vaccine strategy, Prime and Spike, based on unadjuvanted intranasal spike boosting that leverages existing immunity generated by primary vaccination to elicit mucosal immune memory within the respiratory tract. We show that Prime and Spike induces robust T resident memory cells, B resident memory cells and IgA at the respiratory mucosa, boosts systemic immunity, and completely protects mice with partial immunity from lethal SARS-CoV-2 infection. Using divergent spike proteins, Prime and Spike enables induction of cross-reactive immunity against sarbecoviruses without invoking original antigenic sin.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Unadjuvanted intranasal spike vaccine booster elicits robust protective mucosal immunity against sarbecoviruses

Mao

Israelow

Suberi

et al. 2022

Preprint

Self Cite

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“…34 Therefore, an efficient delivery system that facilitates endocytosis and siRNA accumulation to interfere with specific genes in vivo is needed. 35,36 Numerous materials, such as viruses, cationic liposomes, inorganic nanoparticles, and polymers, have been developed to improve siRNA delivery. 36,37 Lately, AuNCs with excellent biocompatibility, low/ non-cytotoxicity, and good stability have drawn increased attention to their potential for gene delivery.…”

Section: Discussionmentioning

confidence: 99%

“…35,36 Numerous materials, such as viruses, cationic liposomes, inorganic nanoparticles, and polymers, have been developed to improve siRNA delivery. 36,37 Lately, AuNCs with excellent biocompatibility, low/ non-cytotoxicity, and good stability have drawn increased attention to their potential for gene delivery. [38][39][40] Hence, self-assembled AuNC-siRNA was fabricated to achieve effective and convenient intra-articular IKKb/NF-kB pathway silencing.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of IKKβ/NF-κB signaling facilitates tendinopathy healing by rejuvenating inflamm-aging induced tendon-derived stem/progenitor cell senescence

Wang

Zhou

Song

et al. 2022

Molecular Therapy - Nucleic Acids

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Degenerative rotator cuff tendinopathy (RCT) is a chronic tendon disease caused by degeneration and inflammation, which often affects the elderly population. Mesenchymal stem cell senescence is generally recognized as an important pathophysiological mechanism in many age-related skeletal diseases. Herein, we collected human tendon-derived stem/progenitor cells (TSPCs) from degenerative supraspinatus tendons and found that TSPC senescence is closely related to RCT. We further identified that nuclear factor kB (NF-kB) pathway activation is involved in age-related inflammation (inflamm-aging) of degenerative RCT. Moreover, whole genome RNA sequencing revealed that in vitro inhibition of the I kappa B kinase b (IKKb)/NF-kB signaling pathway could reverse the aged TSPC phenotype with decreased TSPC senescence and increased tenogenic potential. To achieve effective in vivo inhibition of IKKb/NF-kB signaling, we fabricated IKKb small interfering RNA (siRNA)-loaded gold nanoclusters (AuNC-siRNA) for efficient and convenient intra-articular delivery of IKKb siRNA. We found that AuNC-siRNA prevented inflamm-aging-induced TSPC senescence and dysfunction in a degenerative RCT aged rat model. Together, these data show that inflamm-aging causes degenerative RCT through inducing TSPC senescence, which can be reversed by blocking the IKKb/ NF-kB pathway in vivo. Thus, our study provides a promising therapeutic strategy for degenerative RCT via intra-articular delivery of IKKb siRNA using AuNCs.

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“…It was essential to optimize the PEGylation because the addition of low concentrations of PACE-PEG to PACE improved polyplex stability but prohibited transfection in vitro. By contrast, the effects of PACE-PEG in vivo were different depending on the delivery route, and low concentrations of PACE-PEG significantly increased inhalation delivery to the lungs [47]. Interestingly, in an attempt to deliver mRNA to the kidneys, nanomicelles were formed by the self-assembly of mRNA and PEG-polyamino acid PAsp(DET) block copolymers.…”

Section: Efforts To Improve Delivery Efficiencymentioning

confidence: 99%

Advances in Nanoparticles for Effective Delivery of RNA Therapeutics

et al. 2022

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RNA therapeutics, including messenger RNA (mRNA) and small interfering RNA (siRNA), are genetic materials that mediate the translation of genetic direction from genes to induce or inhibit specific protein production. Although the interest in RNA therapeutics is rising globally, the absence of an effective delivery system is an obstacle to the clinical application of RNA therapeutics. Additionally, immunogenicity, short duration of protein expression, unwanted enzymatic degradation, and insufficient cellular uptake could limit the therapeutic efficacy of RNA therapeutics. In this regard, novel platforms based on nanoparticles are crucial for delivering RNAs to the targeted site to increase efficiency without toxicity. In this review, the most recent status of nanoparticles as RNA delivery vectors, with a focus on polymeric nanoparticles, peptidederived nanoparticles, inorganic nanoparticles, and hybrid nanoparticles, is discussed. These nanoparticular platforms can be utilized for safe and effective RNA delivery to augment therapeutic effects. Ultimately, RNA therapeutics encapsulated in nanoparticle-based carriers will be used to treat many diseases and save lives.

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PEGylation of poly(amine-co-ester) polyplexes for tunable gene delivery

Cited by 47 publications

References 40 publications

Unadjuvanted intranasal spike vaccine booster elicits robust protective mucosal immunity against sarbecoviruses

Unadjuvanted intranasal spike vaccine booster elicits robust protective mucosal immunity against sarbecoviruses

Inhibition of IKKβ/NF-κB signaling facilitates tendinopathy healing by rejuvenating inflamm-aging induced tendon-derived stem/progenitor cell senescence

Advances in Nanoparticles for Effective Delivery of RNA Therapeutics

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