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Biophysical characterization of HPAEs differing in branched structure. a All the polymers have strong and similar DNA binding affinity. b All the polyplexes have sizes < 250 nm and LPAE/DNA polyplexes have a smaller size in comparison with HPAE/DNA counterparts. c As the branching degree increases, the zeta potential of polyplexes increases and reaches at a stable level at 12 mV. d LPAE/DNA and HPAE-3/DNA polyplexes manifest substantially different morphologies, the former is spherical while the latter is toroidal, the scale bars represent 100 nm. e HPAE-3/DNA polyplexes show much stronger cellular uptake and endo/lysosomal escape efficiency, compared to the LPAE/DNA counterparts. The scale bars represent 20 μm. Data are shown as average ± SD; n = 4
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Current therapies for most neurodegenerative disorders are only symptomatic in nature and do not change the course of the disease. Gene therapy plays an important role in disease modifying therapeutic strategies. Herein, we have designed and optimized a series of highly branched poly(β-amino ester)s (HPAEs) containing biodegradable disulfide units...
Citations
... PbAE is an ideal carrier for delivering anticancer drugs because of its distinct characteristics including biocompatibility, low cytotoxicity, pH-responsiveness, and ease of production. [20][21][22] At physiological pH, PbAE is neutrally hydrophobic, but under acidic conditions, it becomes positively charged and hydrophilic when protonated. This allows for chemical functionalization and the ability to adjust its structure. ...
The environmentally friendly polymerization process was carried out using microwave irradiation without additional solvents or catalysts to produce poly(β-amino ester) (PβAE) which served as a drug delivery system. PβAE was synthesized through Michael addition polymerization of 1,4-butane diol diacrylate and piperazine. Swelling and biodegradation studies were conducted in various solvents and phosphate-buffered saline (PBS, pH 7.4) at 37 °C to evaluate the properties of the polymeric gel. The PβAE matrix demonstrated solubility enhancement for hydrophobic antimicrobial and antitumor-active nicotinamide derivatives (TEINH, APTAT, and MOAPM), controlling their release over 10 days in (PBS). The successful formation of free and loaded PβAE with nicotinamide active materials was confirmed by spectroscopic analysis including Fourier-transform infrared spectroscopy (FT-IR) and scanning electron microscopy (SEM). Optimization and physical descriptor determination via the DFT/B3LYP-631(G) basis set were performed to aid in the biological evaluation of these compounds with elucidation of their physical and chemical interaction between poly(β-amino ester) and nicotinamide drugs.
... Therefore, safe and efficient gene vectors are critical for the development of gene therapy [3]. Owing to its tailorable composition, topological structure and molecular weight (MW), biodegradability, and biocompatibility, polymer, as a promising clinically advanced non-viral vector, has been employed to facilitate the delivery of DNA, RNA, and protein [4][5][6][7][8][9][10][11][12]. In addition to monomer composition and MW, topological structure has significant effects on the gene transfection performance of cationic polymers. ...
... In 2018, Zeng et al. combined the linear oligomer branching strategy to prepare a new linear-branched hybrid poly(β-amino ester) (LBPAE), which provides an important platform for the synthesis of structurally precise branched polymers [79]. Liu et al. designed and optimized a new disulfide in backbone and grafted guanidine moieties to prepare HAPEs via iteratively optimizing reaction strategies, exhibited high transfection efficiency in adipose derived stem cells (ADSCs) and astrocytes [4]. ...
... In 2020, Wang et al., prepared a series of HPAEs via "A2 + B3 + C2" and "A2 + B4 + C2" strategies, and confirmed that branching strategies showed a significant impact on DNA condensation, cell uptake, and DNA transfection [115]. Meanwhile, various functionalized modifications of HPAEs, such as responsive degradation, cancer cell targeting [116], pH and temperature responsive release [117], the balance of hydrophilicity and hydrophobicity [118], guanidine moiety modifications [4] have been employed for the genetic material delivery, especially for difficult-to-transfect cells. Compared to the limitations of single functionalization, iterative optimization could comprehensively improve the transfection performance of HPAEs, which becomes an important strategy for the optimized multifunctional polymerbased vectors [4]. ...
Currently, many types of non-linear topological structure polymers, such as brush-shaped, star, branched and dendritic structures, have captured much attention in the field of gene delivery and nanomedicine. Compared with linear polymers, non-linear topological structural polymers offer many advantages, including multiple terminal groups, broad and complicated spatial architecture and multi-functionality sites to enhance gene delivery efficiency and targeting capabilities. Nevertheless, the complexity of their synthesis process severely hampers the development and applications of nonlinear topological polymers. This review aims to highlight various synthetic approaches of non-linear topological architecture polymers, including reversible-deactivation radical polymerization (RDRP) including atom-transfer radical polymerization (ATRP), nitroxide-mediated polymerization (NMP), reversible addition-fragmentation chain transfer (RAFT) polymerization, click chemistry reactions and Michael addition, and thoroughly discuss their advantages and disadvantages, as well as analyze their further application potential. Finally, we comprehensively discuss and summarize different non-linear topological structure polymers for genetic materials delivering performance both in vitro and in vivo, which indicated that topological effects and nonlinear topologies play a crucial role in enhancing the transfection performance of polymeric vectors. This review offered a promising guideline for the design and development of novel nonlinear polymers and facilitated the development of a new generation of polymer-based gene vectors.
... Wenxin Wang's group has prepared several HPBAE nanoparticles to load DNA and found that HPBAE as transfection reagent outperformed Lipofectatmine 2000 and PEI in several kinds of cells. 44,45 In this study, HPBAE loaded with mRNA also achieved relatively high transfection rate in DCs and outperformed the optimized commercial PEI reagent (Figure 2E-H). BMDCs were hard-to-transfect cells while HPBAE could enhance the transfection probably due to the excellent endosome escape ability and adjuvant effect on stimulating DCs, which might change the nanoparticle uptake and mRNA translation. ...
Cancer vaccines combined with immune checkpoint blockades (ICB) represent great potential application, yet the insufficient tumor antigen presentation and immature dendritic cells hinder improved efficacy. Here, a hybrid nano vaccine composed by hyper branched poly(beta‐amino ester), modified iron oxide nano adjuvant and messenger RNA (mRNA) encoded with model antigen ovalbumin (OVA) is presented. The nano vaccine outperforms three commercialized reagents loaded with the same mRNA, including Lipofectamine MessengerMax, jetPRIME, and in vivo‐jetRNA in promoting dendritic cells’ transfection, maturation, and peptide presentation. In an OVA‐expressing murine model, intratumoral administration of the nano vaccine significantly induced macrophages and dendritic cells’ presenting peptides and expressing co‐stimulatory CD86. The nano vaccine also elicited strong antigen‐specific splenocyte response and promoted CD8+ T cell infiltration. In combination with ICB, the nano vaccine aroused robust tumor suppression in murine models with large tumor burdens (initial volume >300 mm³). The hybrid mRNA vaccine represents a versatile and readily transformable platform and augments response to ICB.
... These HPAEs possessed tailorable composition, structure, molecular weight (MW), biodegradability, high stability, and excellent biocompatibility [11]. The one-pot copolymerization of amine (A2), triacrylate (B3), and diacrylate (C2) not only delayed gelation during the polymerization process but also resulted in three-dimensional (3D) topology and multiple terminal groups in the HPAEs [12,13]. Through optimization, the HPAE exhibited showed up to 8521-fold enhancement in gene transfection efficiency compared to the corresponding linear poly(β-amino ester)s (LPAEs) in vitro [10]. ...
... Nevertheless, utilizing the generalizable one-pot Michael addition strategy, all HPAEs exhibited broad molecular weight distribution (MWD) with the polydispersity index (Đ) values up to 12.0 [12,[16][17][18], leaded to poor homogeneity and stability, presenting additional challenges in understanding the mechanistic impact of MW on their gene transfection activity, which was not conducive for nano-sized polyplexes to efficiently overcome various extracellular and intracellular barriers, as well as clinical approval of the products. In 2023, we employed a step-by-step precipitation strategy to fractionate HPAEs with a similar composition and relatively narrow Đ from the crude polymer and preliminarily compared their gene transfection performance in vitro [16]. ...
Extensive efforts have been dedicated to enhancing the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in cancer cells for the development of effective cancer treatments. However, highly safe and efficient delivery of TRAIL gene remains a significant challenge, especially using cationic polymers. Here, a series of highly branched-linear poly(β-amino ester)s (H-LPAEs) are developed through a unique oligomer branching strategy. H-LPAEs exhibit a more uniform distribution of linear segments and branching units, leading to excellent DNA condensation and favorable physicochemical properties of H-LPAE/DNA polyplexes. In SW1353 and BMSC cells, the optimized H-LPAEs, H-LPAEB4−S5−TMPTA, achieves superior gene transfection efficiency of 58.0% and 33.4%, which were 2.5-fold and 2.0-fold higher than that of the leading commercial gene transfection reagent, Lipofectamine 3000. Excitingly, H-LPAEB4−S5−TMPTA mediated 56.7% and 28.1% cell apoptosis in HepG2 cells and HeLa cells highlighting its potential application in cancer gene therapy. In addition, locally administered H-LPAEB4−S5−TMPTA delivered TRAIL DNA to HepG2 xenograft tumors and inhibited tumor growth in vivo. This study not only proposes a novel strategy for synthesizing poly(β-amino ester)s with a unique branched-linear topology but also identifies a promising candidate for highly efficient TRAIL gene transfection.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12951-023-02169-7.
... One solution is the use of the nerve growth factor (NGF). NGF is a cytokine that promotes neuronal growth and regeneration, and plays a vital role in nervous system following injury [78][79][80]. NGF enhances the speed and quality of nerve regeneration, thereby facilitating injury repair. Another solution is to use adhesives instead of traditional suturing techniques [81][82][83]. ...
... It was reported that PEI polymers with low molecular weight was less cytotoxic compared to high molecular weight PEI, but the transfection efficacy was also decreased [73,74]. Researchers continue to develop next-generation cationic polymers, such as poly(β-amino ester) (PBAE) polymers, which are proved to be less cytotoxic and more efficient than PEI [75][76][77][78]. Zwitterionic biomaterials with oppositely charged groups have drawn great attention in many fields, like drug delivery, diagnosis, biosensors, and coating. ...
RNA-based therapeutics have shown great promise in various medical applications, including cancers, infectious diseases, and metabolic diseases. The recent success of mRNA vaccines for combating the COVID-19 pandemic has highlighted the medical value of RNA drugs. However, one of the major challenges in realizing the full potential of RNA drugs is to deliver RNA into specific organs and tissues in a targeted manner, which is crucial for achieving therapeutic efficacy, reducing side effects, and enhancing overall treatment efficacy. Numerous attempts have been made to pursue targeting, nonetheless, the lack of clear guideline and commonality elucidation has hindered the clinical translation of RNA drugs. In this review, we outline the mechanisms of action for targeted RNA delivery systems and summarize four key factors that influence the targeting delivery of RNA drugs. These factors include the category of vector materials, chemical structures of vectors, administration routes, and physicochemical properties of RNA vectors, and they all notably contribute to specific organ/tissue tropism. Furthermore, we provide an overview of the main RNA-based drugs that are currently in clinical trials, highlighting their design strategies and tissue tropism applications. This review will aid to understand the principles and mechanisms of targeted delivery systems, accelerating the development of future RNA drugs for different diseases.
... Compared to linear polymers, the nanoparticles formed by cyclic topology polymers and gene are more compact and smaller size [16]. For example, highly branched polymers, due to their large number of terminal groups, three-dimensional (3D) spatial structure, and strong DNA binding, have exhibited higher gene encapsulation capability compared to linear polymers [17]. Many investigations have demonstrated that nanoparticle sizes that are neither too small nor too large are not favourable for gene transfection. ...
... Multi-functional HPAEs can be designed and synthesized by incorporating multiple functional groups into the same polymer chain. For instance, Liu et al. have designed and prepared multi-functional HPAEs with superior transfection efficiency and low cytotoxicity for difficult-to-transfect cells [17]. They used an iterative optimization approach that involved three aspects: branched structure, degradation, and cell uptake. ...
Gene therapy holds great promise for treating a multitude of inherited and acquired diseases by delivering functional genes, comprising DNA or RNA, into targeted cells or tissues to elicit manipulation of gene expression. However, the clinical implementation of gene therapy remains substantially impeded by the lack of safe and efficient gene delivery vehicles. This review comprehensively outlines the novel fastest-growing and efficient non-viral gene delivery vectors, which include liposomes and lipid nanoparticles (LNPs), highly branched poly(β-amino ester) (HPAE), single-chain cyclic polymer (SCKP), poly(amidoamine) (PAMAM) dendrimers, and polyethyleneimine (PEI). Particularly, we discuss the research progress, potential development directions, and remaining challenges. Additionally, we provide a comprehensive overview of the currently approved non-viral gene therapeutics, as well as ongoing clinical trials. With advances in biomedicine, molecular biology, materials science, non-viral gene vectors play an ever-expanding and noteworthy role in clinical gene therapy.
... PBAEs are considered to be promising polymers in biomedical applications owing to their excellent biocompatibility and biodegradability [41][42][43][44]. As cationic polymer structures, PBAE-based nanoparticles have shown high potential for gene delivery [45][46][47][48]. Recent studies showed effective delivery of mRNAs and DNAs through pulmonary or systemic delivery using the polymer-lipid nanoparticles combined with PBAEs and lipid molecules via microfluidic devices [49][50][51][52]. ...
Endothelial cell dysfunction occurs in a variety of acute and chronic pulmonary diseases including pulmonary hypertension, viral and bacterial pneumonia, bronchopulmonary dysplasia, and congenital lung diseases such as alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). To correct endothelial dysfunction, there is a critical need for the development of nanoparticle systems that can deliver drugs and nucleic acids to endothelial cells with high efficiency and precision. While several nanoparticle delivery systems targeting endothelial cells have been recently developed, none of them are specific to lung endothelial cells without targeting other organs in the body. In the present study, we successfully solved this problem by developing non-toxic poly(β-amino) ester (PBAE) nanoparticles with specific structure design and fluorinated modification for high efficiency and specific delivery of nucleic acids to the pulmonary endothelial cells. After intravenous administration, the PBAE nanoparticles were capable of delivering non-integrating DNA plasmids to lung microvascular endothelial cells but not to other lung cell types. IVIS whole body imaging and flow cytometry demonstrated that DNA plasmid were functional in the lung endothelial cells but not in endothelial cells of other organs. Fluorination of PBAE was required for lung endothelial cell-specific targeting. Hematologic analysis and liver and kidney metabolic panels demonstrated the lack of toxicity in experimental mice. Thus, fluorinated PBAE nanoparticles can be an ideal vehicle for gene therapy targeting lung microvascular endothelium in pulmonary vascular disorders.
... In light of the growing demand for treatment methods for neurodegenerative diseases, stem cells can be used in this area to treat a variety of neurodegenerative disorders [166]. The current state of cell-based therapies for neurological disorders must be examined in order to advance the field [167]. ...
Neurodegenerative diseases are characterized by the progressive loss of neurons and intricate interactions between different cell types within the affected regions. Reliable biomarkers that can accurately reflect disease activity, diagnose, and monitor the progression of neurodegenerative diseases are crucial for the development of effective therapies. However, identifying suitable biomarkers has been challenging due to the heterogeneous nature of these diseases, affecting specific subsets of neurons in different brain regions. One promising approach for promoting brain regeneration and recovery involves the transplantation of mesenchymal stem cells (MSCs). MSCs have demonstrated the ability to modulate the immune system, promote neurite outgrowth, stimulate angiogenesis, and repair damaged tissues, partially through the release of their extracellular vesicles (EVs). MSC-derived EVs retain some of the therapeutic characteristics of their parent MSCs, including their ability to regulate neurite outgrowth, promote angiogenesis, and facilitate tissue repair. This review aims to explore the potential of MSC-derived EVs as an emerging therapeutic strategy for neurodegenerative diseases, highlighting their role in modulating disease progression and promoting neuronal recovery. By elucidating the mechanisms by which MSC-derived EVs exert their therapeutic effects, we can advance our understanding and leverage their potential for the development of novel treatment approaches in the field of neurodegenerative diseases.
... Recently, more and more attention has been paid to gene delivery materials based on hyperbranched polymers, including hyperbranched PEI, polylysine, and PBAE, etc. [26][27][28][29][30]. Hyperbranched polymers offer numerous advantages over their linear counterparts, including enhanced complexation efficiency with genes, improved cellular uptake efficiency, and efficient escape from endosomes [27]. ...
Despite the availability of mRNA vaccines utilizing LNP delivery technology, there remains a pressing need for the development of non-viral mRNA delivery vectors that are both more efficient and safe. we present a novel hyperbranched poly(amine-co-ester) (HBPA) system, catalyzed by immobilized lipase, for efficient in vitro and in vivo mRNA delivery. By polymerizing four monomers, we successfully synthesized HBPA with a hyperbranched structure, and subsequent modification of the end groups resulted in HBPA-E. Comparative evaluations revealed that HBPA-E outperforms linear PACE and the commercial transfection reagent Lipofectamine MessengerMAX (LipoMM) in terms of intracellular delivery efficiency, while demonstrating lower cytotoxicity. Furthermore, the in vivo pulmonary delivery efficiency of HBPA-E was significantly superior to that of LPA-E and the commercial in vivo delivery reagent in vivo-JetRNA. Finally, the HBPA-E can be easily dissolved in ethanol, and its mRNA formulation can be employed as a freeze-drying formulation, making it a valuable candidate for future clinical applications of mRNA delivery.
