bims-novged Biomed News
on Non-viral vectors for gene delivery
Issue of 2021‒09‒05
twelve papers selected by
Benjamin Winkeljann
Ludwig-Maximilians University
  1. Pharmacokinetics and Biodistribution Analysis of Small Interference RNA for Silencing Tissue Transglutaminase-2 in Celiac Disease After Oral Administration in Mice Using Gelatin-Based Multicompartmental Delivery Systems.
  2. Degradable cationic polyesters via ring-opening copolymerization of valerolactones as nanocarriers for the gene delivery.
  3. An RNA/DNA hybrid origami-based nanoplatform for efficient gene therapy.
  4. Acylation of antimicrobial peptide-plasmid DNA vectors formulation for efficient gene delivery in cancer therapy.
  5. Niosomes-based gene delivery systems for effective transfection of human mesenchymal stem cells.
  6. Arf6-mediated macropinocytosis-enhanced suicide gene therapy of C16TAB-condensed Tat/pDNA nanoparticles in ovarian cancer.
  7. A two-pronged approach to regulate the behaviors of ECs and SMCs by the dual targeting-nanoparticles.
  8. Potential of chitosan/alginate nanoparticles as a non-viral vector for gene delivery: Formulation and optimization using D-optimal design.
  9. Folate targeted hybrid lipo-polymeric nanoplexes containing docetaxel and miRNA-34a for breast cancer treatment.
  10. Integrating disulfides into a polyethylenimine gene carrier selectively boosts significant transfection activity in lung tissue enabling robust IL-12 gene therapy against metastatic lung cancers.
  11. High-throughput screening of nanoparticles in drug delivery.
  12. The core composition of DNA block copolymer micelles dictates DNA hybridization properties, nuclease stabilities, and cellular uptake efficiencies.
  1. Bioelectricity. 2020 Jun 01. 2(2): 167-174
    Pharmacokinetics and Biodistribution Analysis of Small Interference RNA for Silencing Tissue Transglutaminase-2 in Celiac Disease After Oral Administration in Mice Using Gelatin-Based Multicompartmental Delivery Systems.
    Husain Z Attarwala, Kanika Suri, Mansoor M Amiji.
      Background: RNA interference (RNAi) therapy has tremendous potential in treating diseases that are characterized by overexpression of genes. However, the biggest challenge to utilize the therapy is to engineer delivery systems that can efficiently transport small interfering RNA (siRNA) to appropriate target sites. Our objective in this study was to develop and evaluate multi-compartmental systems for the oral delivery of siRNA that targets the overexpressed TG2 gene (TG2-siRNA) in the small intestine for the treatment of celiac disease (CD). Materials and Methods: Two types of multicompartmental systems were developed and evaluated: (1) a solid-in-solid multicompartmental system featuring "nanoparticle in microsphere oral system (NiMOS)" where type B gelatin nanoparticles containing TG2-siRNA (TG2-NiMOS) were encapsulated within poly(ɛ-caprolactone) (PCL) based microspheres, and (2) a solid-in-liquid multicompartmental system, "Nanoparticle-in-Emulsion (NiE)" consisting of type-B gelatin nanoparticles containing TG2-siRNA encapsulated within safflower oil containing water-in-oil-in-water (W/O/W) multiple emulsion (TG2-NiE). Results: Evaluation of the biodistribution and pharmacokinetics (PK) after a single oral dose of siRNA containing multicompartmental systems to C57BL/6 mice showed that TG2-siRNA was delivered to the small intestine (duodenum, jejunum and ileum), and colon with minimal systemic exposure via both TG2-NiE and TG2-NiMOS systems. TG2-siRNA exposure (AUC0-t) in the duodenum, jejunum, ileum and colon was 56.4-, 34.3-, 85.5- and 35.5-fold greater for the TG2-NiMOS formulation, relative to the TG2-NiE formulation. Conclusion: The results of this study suggest that TG2-NiMOS formulation was more superior than TG2-NiE formulation in facilitating intestinal delivery of siRNA via the oral route of administration and can be potentially used in the treatment of CD.
    Keywords:  gelatin nanoparticles; multicompartmental delivery; oral administration; pharmacokinetic and biodistribution; small interference RNA
    DOI:  https://doi.org/10.1089/bioe.2020.0008
  2. Bioorg Chem. 2021 Aug 21. pii: S0045-2068(21)00676-3. [Epub ahead of print]116 105299
    Degradable cationic polyesters via ring-opening copolymerization of valerolactones as nanocarriers for the gene delivery.
    Xu-Ying Liu, Jing-Bo Yang, Ting-Ting Duan, Cheng-Yan Wu, Quan Tang, Zhong-Lin Lu, Lan He, Wan Sun.
      The development of cationic polymers as non-viral gene vectors has been hurdled by their high toxicity, thus degradable and biocompatible polymers are urgently demanded. Herein, five polyesters (B3a-B3e) were synthesized based on the ring-opening copolymerization between α-allyl-δ-valerolactone and δ-valerolactone derivatives decorated with alkyl or alkoxyl chains of different lengths, followed by the modification with 1,5,9-triazacyclododecyl ([12]aneN3) through thiol-ene click reactions. The five polyesters effectively condensed DNA into nanoparticles. Of them, B3a with a shorter alkyl chain and B3d with more positive charged units showed stronger DNA condensing performance and can completely retard the migration of DNA at N/P = 1.6 in the presence of DOPE. B3b/DOPE with a longer alkyl chain exhibited the highest transfection efficiency in HeLa cells with 1.8 times of 25 kDa PEI, while B3d/DOPE with more positive charged units exhibited highest transfection efficiency in A549 cells with 2.3 times of 25 kDa PEI. B3b/DOPE and B3d/DOPE successfully delivered pEGFP into zebrafish, which was superior to 25 kDa PEI (1.5 folds and 1.1 folds, respectively). The cytotoxicity measurements proved that the biocompatibility of these polyesters was better than 25 kDa PEI, due to their degradable property in acid environment. The results indicated that these cationic polyesters can be developed as potential non-viral gene vectors for DNA delivery.
    Keywords:  Degradable polyester; Gene transfection; Non-viral gene vector; Valerolactone; [12]aneN(3)
    DOI:  https://doi.org/10.1016/j.bioorg.2021.105299
  3. Nanoscale. 2021 Aug 14. 13(30): 12848-12853
    An RNA/DNA hybrid origami-based nanoplatform for efficient gene therapy.
    Xiaohui Wu, Qing Liu, Fengsong Liu, Tiantian Wu, Yingxu Shang, Jianbing Liu, Baoquan Ding.
      Nucleic acid nanostructures are promising biomaterials for the delivery of homologous gene therapy drugs. Herein, we report a facile strategy for the construction of target mRNA (scaffold) and antisense (staple strands) co-assembled RNA/DNA hybrid "origami" for efficient gene therapy. In our design, the mRNA was folded into a chemically well-defined nanostructure through RNA-DNA hybridization with high yield. After the incorporation of an active cell-targeting aptamer, the tailored RNA/DNA hybrid origami demonstrated efficient cellular uptake and controllable release of antisenses in response to intracellular RNase H digestion. The biocompatible RNA/DNA origami (RDO) elicited a noticeable inhibition of cell proliferation based on the silencing of the tumor-associated gene polo-like kinase 1 (PLK1). This RDO-based nanoplatform provides a novel strategy for the further development of gene therapy.
    DOI:  https://doi.org/10.1039/d1nr00517k
  4. Colloids Surf B Biointerfaces. 2021 Aug 27. pii: S0927-7765(21)00513-0. [Epub ahead of print]208 112069
    Acylation of antimicrobial peptide-plasmid DNA vectors formulation for efficient gene delivery in cancer therapy.
    Yue Li, Yue Sun, Weibing Dong, Chengdong Zhu, Yue Guan, Dejing Shang.
      Antimicrobial peptides/DNA complexes were designed based on AMPs chensinin-1b and its corresponding lipo-chensinin-1b conjugated with an aliphatic acid with different chain lengths and therapeutic genes. The main goal of such a complex includes two aspects: first, antimicrobial peptides deliver therapeutic genes to cancer cells and genes expressed in targeted tissue for cancer gene therapy, and, second, the antimicrobial peptide kills cancer cells when used alone as an anticancer agent. This study presents a model composed of chensinin-1b and its lipo-chensinin-1b and eGFP plasmids, which were used as reporter genes, and the final peptide/eGFP plasmid complexes were analyzed by TEM and DLS. The gene transfection efficiency of the complex was evaluated by a microplate reader, FACS and CLSM. Compared with Lipo2000, the antimicrobial peptide showed specific selectivity for transfection against cancer cells and mammalian cells. The peptides chensinin-1b and lipo-chensinin-1b binding with the eGFP plasmid displayed optimal transfection efficiencies at a mass ratio of 8. In addition, PA-C1b can deliver p53-eGFP plasmids into MCF-7 cancer cells, and the proliferation of cells was inhibited and even caused cell death. Overall, PA-C1b was screened and found to have the highest transfection efficiency for gene delivery and good cellular uptake capability. The in vivo transfection ability of PA-C1b was investigated using a tumor-bearing mouse model, and the transfection efficiency reflected by the fluorescence of expressed GFP was determined by in vivo imaging. Conclusively, the antimicrobial peptide PA-C1b could be used as the nonviral vector with high efficiency for cancer gene therapy.
    Keywords:  Antimicrobial peptide; Cancer gene therapy; Green fluorescent protein; Non-viral vectors; p53
    DOI:  https://doi.org/10.1016/j.colsurfb.2021.112069
  5. Mater Sci Eng C Mater Biol Appl. 2021 Sep;pii: S0928-4931(21)00446-X. [Epub ahead of print]128 112307
    Niosomes-based gene delivery systems for effective transfection of human mesenchymal stem cells.
    Natalia Carballo-Pedrares, Axel Kattar, Angel Concheiro, Carmen Alvarez-Lorenzo, Ana Rey-Rico.
      Gene transfer to mesenchymal stem cells (MSCs) has arisen as a powerful approach to increase the therapeutic potential of this effective cell population. Over recent years, niosomes have emerged as self-assembled carriers with promising performance for gene delivery. The aim of our work was to develop effective niosomes-based DNA delivery platforms for targeting MSCs. Niosomes based on 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA; 0, 7 or 15%) as cationic lipid, cholesterol as helper lipid, and polysorbate 60 as non-ionic surfactant, were prepared using a reverse phase evaporation technique. Niosomes dispersions (filtered or not) and their corresponding nioplexes with a lacZ plasmid were characterized in terms of size, charge, protection, and complexation abilities. DOTMA concentration had a large influence on the physicochemical properties of resulting nioplexes. Transfection efficiency and cytotoxic profiles were assessed in two immortalized cell lines of MSCs. Niosomes formulated with 15% DOTMA provided the highest values of β-galactosidase activity, being similar to those achieved with Lipofectamine®, but showed less cytotoxicity. Filtration of niosomes dispersions before adding to the cells resulted in a loss of their biological activities. Storage of niosomes formulations (for 30 days at room temperature) caused minor modification of their physicochemical properties but also attenuated the transfection capability of the nioplexes. Differently, addition of the lysosomotropic agent sucrose into the culture medium during transfection or to the formulation itself improved the transfection performance of non-filtered niosomes. Indeed, steam heat-sterilized niosomes prepared in sucrose medium demonstrated transfection capability.
    Keywords:  DOTMA; Gene transfer; MSCs; Niosomes; Stability.; Sucrose
    DOI:  https://doi.org/10.1016/j.msec.2021.112307
  6. Nanoscale. 2021 Sep 02. 13(34): 14538-14551
    Arf6-mediated macropinocytosis-enhanced suicide gene therapy of C16TAB-condensed Tat/pDNA nanoparticles in ovarian cancer.
    Zhe Sun, Jinhai Huang, Linjia Su, Jing Li, Fangzheng Qi, Huishan Su, Yanan Chen, Qing Zhang, Qiangzhe Zhang, Zongjin Li, Sihe Zhang.
      The use of cell-penetrating peptides (CPPs), typically HIV-Tat, to deliver therapeutic genes for cancer treatment is hampered by the inefficient delivery and complicated uptake route of plasmid DNA (pDNA). On the one hand, surface charges, particle size and shape essentially contribute to the endocytosis pathway of Tat/pDNA nanocomplexes, and on the other hand, endogenous cellular factors dominantly determine their intracellular trafficking fate and biological outcome. Recent advances in surfactant-modified nanomaterial and dual molecular imaging technology have offered new opportunities for suicide gene therapy. In this study, we employed the cationic surfactant C16TAB to further condense Tat/pDNA nanocomplexes for improving their delivery efficiency and tested the therapeutic effect of Tat/pDNA/C16TAB (T-P-C) nanoparticles carrying the GCV-converted HSV-ttk suicide gene for ovarian cancer. The cellular endocytosis pathway and underlying signal mechanism of T-P-C nanoparticles were further determined. The obtained T-P-C nanoparticles exhibited a small size, positive surface charge, irregular granular shape and high pDNA encapsulation efficiency. The in vitro experiments showed that T-P-C nanoparticles mainly used the macropinocytosis pathway for uptake in ovarian cancer cells. Their internalization and payload gene expression were controlled by the Arf6 GTPase-dependent, Rab GTPase-activated signal axis. Further in vivo molecular imaging based on DF (Fluc-eGFP)-TF (RFP-Rluc-HSV-ttk) system showed that T-P-C nanoparticles significantly increased the targeted delivery and suicide gene therapy in a mouse model xenografted with human ovarian cancer. More importantly, Arf6-mediated macropinocytosis remarkably enhanced the delivery efficiency and suicide gene therapy effect of T-P-C nanoparticles. Therefore, these C16TAB-condensed Tat/pDNA nanoparticles combined with the dual molecular imaging strategy provides a novel intracellular delivery platform for high-efficient, precise suicide gene therapy of ovarian cancer.
    DOI:  https://doi.org/10.1039/d1nr03974a
  7. Colloids Surf B Biointerfaces. 2021 Aug 26. pii: S0927-7765(21)00512-9. [Epub ahead of print]208 112068
    A two-pronged approach to regulate the behaviors of ECs and SMCs by the dual targeting-nanoparticles.
    Xiaoyu Wang, Bin Gao, Xiang-Kui Ren, Jintang Guo, Shihai Xia, Wencheng Zhang, Cheng Yang, Yakai Feng.
      Inhibiting vascular restenosis remains a tricky challenge for the postoperative development of cardiovascular interventional therapy. The ideal approaches should activate endothelial cells (ECs) and restrain smooth muscle cells (SMCs), however, they are commonly contradictory. Herein, a strategy was developed for synchronizing ECs promotion and SMCs inhibition by codelivery DNA and siRNA for combination therapy. Thus, an easy and efficient strategy integrated dual-superiorities of precise targeting and dual therapeutic genes to precisely regulate the behaviors of ECs and SMCs. The ECs-targeting REDV peptide and SMCs-targeting VAPG peptide grafted anionic polymers were used to surface-functionalize the delivery nanoplatforms for vascular endothelial growth factor (VEGF) plasmids and ERK2 siRNA delivery, respectively. The dual targeting-nanoparticles were prepared by physical mixing method, and their outstanding advantages were confirmed by the co-culture experiments. In comparison with single targeting-nanoparticles and dual non-targeting-nanoparticles, the dual targeting-nanoparticles simultaneously enhanced ECs proliferation/migration and restrained SMCs proliferation/migration. Moreover, the dual targeting-nanoparticles group manifested the highest VEGF expression in ECs and the lowest ERK2 expression in SMCs. In summary, the two-pronged strategy with dual targeting-nanoparticles provides a valuable cornerstone for synchronizing ECs promotion and SMCs inhibition.
    Keywords:  Co-culture; Endothelial cells; Gene delivery; Smooth muscle cells; Targeting peptide
    DOI:  https://doi.org/10.1016/j.colsurfb.2021.112068
  8. Mater Sci Eng C Mater Biol Appl. 2021 Sep;pii: S0928-4931(21)00401-X. [Epub ahead of print]128 112262
    Potential of chitosan/alginate nanoparticles as a non-viral vector for gene delivery: Formulation and optimization using D-optimal design.
    Maryam Zohri, Ehsan Arefian, Hamid Akbari Javar, Taraneh Gazori, Seyed Hamid Aghaee-Bakhtiari, Mojtaba Taheri, Yousef Fatahi, Amir Azadi, Mohammad Reza Khoshayand, Mohammad Hossein Ghahremani.
      Chitosan/alginate (Chi/Alg) nanoparticles as a non-viral vector for the Smad4 encoding plasmid were optimized utilizing D-optimal design based on the nanoparticles/plasmid ratio, Chi/Alg MW, and preparation method type. Following the optimization and validation of the best formula, morphology studies and FTIR measurements were performed to evaluate the optimized Chi/Alg/S NPs. Toxicity (MTT assay) and transfection studies were performed for the best formula in comparison with Lipofectamine 2000, and Polyethyleneimine (PEI) and evaluated using Green Fluorescence Protein (GFP) assay, Flow cytometry, and RT-PCR. The model predicted a particle size of 111 nm, loading efficacy (LE) of 43%, cumulative release (CMR) of 39%, the ζ-potential of +50 mV, and PDI of 0.13. The predicted point condition was as follows: NP ratio = 13, Chi/Alg MW ratio = 2.35, and preparation method type = 1. Microscopic findings revealed that the shape of nanoparticles was spherical. The Chi/Alg/S nanoparticles showed no toxicity and transfection efficacy of 29.9% was observed in comparison with Lipofectamine (35.5%) and PEI (30.9%).
    Keywords:  Chitosan/alginate nanoparticles; D-optimal design; Gene transfection; Non-viral vector; Smad4 encoding plasmid
    DOI:  https://doi.org/10.1016/j.msec.2021.112262
  9. Mater Sci Eng C Mater Biol Appl. 2021 Sep;pii: S0928-4931(21)00444-6. [Epub ahead of print]128 112305
    Folate targeted hybrid lipo-polymeric nanoplexes containing docetaxel and miRNA-34a for breast cancer treatment.
    Saurabh Sharma, Sudeep Pukale, Deepak Kumar Sahel, Prabhjeet Singh, Anupama Mittal, Deepak Chitkara.
      In spite of established evidence of the synergistic combination of hydrophobic anticancer molecule and microRNA for breast cancer treatment, their in vivo delivery has not been realized owing to their instability in the biological milieu and varied physicochemical properties. The present work reports folate targeted hybrid lipo-polymeric nanoplexes for co-delivering DTX and miR-34a. These nanoplexes exhibited a mean size of 129.3 nm with complexation efficiency at an 8:1 N/P ratio. The obtained nanoplexes demonstrated higher entrapment efficiency of DTX (94.8%) with a sustained release profile up to 85% till 48 h. Further, an improved transfection efficiency in MDA-MB-231 and 4T1 breast cancer cells was observed with uptake primarily through lipid-raft and clathrin-mediated endocytosis. Further, nanoplexes showed improved cytotoxicity (~3.5-5 folds), apoptosis (~1.6-2.0 folds), and change in expression of apoptotic genes (~4-7 folds) compared to the free treatment group in breast cancer cells. In vivo systemic administration of FA-functionalized DTX and FAM-siRNA-loaded nanoplexes showed an improved area under the curve (AUC) as well as circulation half-life compared to free DTX and naked FAM-labelled siRNA. Acute toxicity studies of the cationic polymer showed no toxicity at a dose equivalent to 10 mg/kg based on the hematological, biochemical, and histopathological examination.
    Keywords:  Breast cancer; Co-delivery; Docetaxel; Lipopolymer; Nanoplexes; miRNA-34a
    DOI:  https://doi.org/10.1016/j.msec.2021.112305
  10. Mater Sci Eng C Mater Biol Appl. 2021 Sep;pii: S0928-4931(21)00498-7. [Epub ahead of print]128 112358
    Integrating disulfides into a polyethylenimine gene carrier selectively boosts significant transfection activity in lung tissue enabling robust IL-12 gene therapy against metastatic lung cancers.
    Juan Liu, Yuhua Yu, Jie Zhao, Peng Zhao, Xuejun Wen, Zhigang Zhuang, Chao Lin.
      Bioreducible polyethylenimines (SSPEIs) are promising non-viral carriers for cancer gene therapy. However, the availability of significant gene transfection activity by SSPEIs remains a challenge. Herein, an essential step was taken to ascertain whether or not the disulfide bonds of SSPEIs play a critical role in promoting significant gene transfection activity in different tissues. Initially, a disulfide-linked linear polyethylenimine (denoted as SSLPEI) consisting of one 5.0 kDa LPEI main chain and three disulfide-linked 5.7 kDa LPEI grafts was designed and prepared to possess similar molecular weight with commercialized 25 kDa LPEI as a positive control. The SSLPEI could induce superior in vitro transfection activity in different cells to the LPEI control as well as low cytotoxicity. Notably, such enhanced in vitro transfection effect by the SSLPEI was more marked in type-II alveolar epithelial cells compared to different cancer cells. In a Balb/c nude mouse model bearing SKOV-3 tumor, the SSLPEI caused parallel level of transgene expression with the LPEI control in the tumor but significantly higher level in the mouse lung. Furthermore, the SSLPEI and LPEI groups afforded an identical antitumor efficacy against the SKOV-3 tumor via intravenous delivery of a shRNA for silencing VEGF expression in the tumor. However, via intravenous delivery of an interleukin-12 (IL-12) gene into metastatic lung cancers in a C57BL/6 mouse model, the SSLPEI group exerted markedly higher IL-12 expression level in the mouse lung and peripheral blood as compared to the LPEI group, thereby boosting IL-12 immunotherapy against the lung metastasis with longer medium survival time. The results of this work elicit that the disulfide bonds of SSPEIs play a pivotal role in enhancing gene transfection activity selectively in the lung tissue rather than solid tumor, enabling high translational potential of SSPEIs for non-viral gene therapy against metastatic lung cancers.
    Keywords:  Disulfide; Interleukin-12; Metastatic lung cancer; Polyethylenimine; Transfection
    DOI:  https://doi.org/10.1016/j.msec.2021.112358
  11. APL Bioeng. 2021 Sep;5(3): 031511
    High-throughput screening of nanoparticles in drug delivery.
    Inês Tomé, Vitor Francisco, Hugo Fernandes, Lino Ferreira.
      The use of pharmacologically active compounds to manage and treat diseases is of utmost relevance in clinical practice. It is well recognized that spatial-temporal control over the delivery of these biomolecules will greatly impact their pharmacokinetic profile and ultimately their therapeutic effect. Nanoparticles (NPs) prepared from different materials have been tested successfully in the clinic for the delivery of several biomolecules including non-coding RNAs (siRNA and miRNA) and mRNAs. Indeed, the recent success of mRNA vaccines is in part due to progress in the delivery systems (NP based) that have been developed for many years. In most cases, the identification of the best formulation was done by testing a small number of novel formulations or by modification of pre-existing ones. Unfortunately, this is a low throughput and time-consuming process that hinders the identification of formulations with the highest potential. Alternatively, high-throughput combinatorial design of NP libraries may allow the rapid identification of formulations with the required release and cell/tissue targeting profile for a given application. Combinatorial approaches offer several advantages over conventional methods since they allow the incorporation of multiple components with varied chemical properties into materials, such as polymers or lipid-like materials, that will subsequently form NPs by self-assembly or chemical conjugation processes. The current review highlights the impact of high-throughput in the development of more efficient drug delivery systems with enhanced targeting and release kinetics. It also describes the current challenges in this research area as well as future directions.
    DOI:  https://doi.org/10.1063/5.0057204
  12. Nanoscale. 2021 Aug 28. 13(32): 13758-13763
    The core composition of DNA block copolymer micelles dictates DNA hybridization properties, nuclease stabilities, and cellular uptake efficiencies.
    Chan-Jin Kim, Ga-Hyun Kim, Eun Hye Jeong, Hyukjin Lee, So-Jung Park.
      Here, we report how the nature of the hydrophobic core affects the molecular interactions of DNA block copolymer assemblies. Three different amphiphilic DNA block copolymers, DNA-b-polystyrene (DNA-b-PS), DNA-b-poly(2-vinylpyridine) (DNA-b-P2VP), and DNA-b-poly(methyl acrylate) (DNA-b-PMA) were synthesized and assembled into spherical micelles composed of a hydrophobic polymer core and DNA corona. Interestingly, DNA block copolymer micelles having different hydrophobic cores exhibited markedly different molecular and biological interactions. DNA-b-PS exhibited higher melting temperature, sharper melting transition, higher stability to nuclease-catalyzed DNA degradation, and higher cellular uptake efficiency compared to DNA-b-P2VP and DNA-b-PMA. The investigation of the self-assembly behavior revealed a much higher aggregation number and DNA density for DNA-b-PS micelles, which explains the superior properties of DNA-b-PS. These results demonstrate that the type of the hydrophobic core polymer, which has been largely overlooked, has a profound impact on the molecular and biological interactions of the DNA shell.
    DOI:  https://doi.org/10.1039/d1nr00756d
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