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Nucleic Acid Hybrids As Advanced Antibacterial Nanocarriers pharmaceutics Review Nucleic Acid Hybrids as Advanced Antibacterial Nanocarriers Sybil Obuobi * and Nataša Škalko-Basnet Drug Transport and Delivery Research Group, Department of Pharmacy, Faculty of Health Sciences, UiT The Arctic University of Norway, Universitetsveien 57, 9037 Tromsø, Norway; [email protected] * Correspondence: [email protected]; Tel.: +47-7766-0261 Received: 11 June 2020; Accepted: 6 July 2020; Published: 8 July 2020 Abstract: Conventional antibiotic therapy is often challenged by poor drug penetration/accumulation at infection sites and poses a significant burden to public health. Effective strategies to enhance the therapeutic efficacy of our existing arsenal include the use of nanoparticulate delivery platforms to improve drug targeting and minimize adverse effects. However, these nanocarriers are often challenged by poor loading efficiency, rapid release and inefficient targeting. Nucleic acid hybrid nanocarriers are nucleic acid nanosystems complexed or functionalized with organic or inorganic materials. Despite their immense potential in antimicrobial therapy, they are seldom utilized against pathogenic bacteria. With the emergence of antimicrobial resistance and the associated complex interplay of factors involved in antibiotic resistance, nucleic acid hybrids represent a unique opportunity to deliver antimicrobials against resistant pathogens and to target specific genes that control virulence or resistance. This review provides an unbiased overview on fabricating strategies for nucleic acid hybrids and addresses the challenges of pristine oligonucleotide nanocarriers. We report recent applications to enhance pathogen targeting, binding and control drug release. As multifunctional next-generational antimicrobials, the challenges and prospect of these nanocarriers are included. Keywords: nucleic acid nanocarriers; hybrids; bacterial infections; antimicrobial resistance; DNA nanostructures 1. Introduction Deadlocked in the evolutionary arms of microorganisms, the competitive medical world struggles to contain the spread of multi-resistant infections, due to the ineffectiveness of conventional antimicrobials [1]. Many of these pathogens result in prolonged illnesses that cause 700,000 estimated deaths each year [2,3]. In Europe alone, recent estimates indicate that more than 670,000 infections in the European Union/ European Economic Area Countries (EU/EEA) are due to antibiotic resistance, with approximately 33,000 deaths annually [4]. As a direct consequence of these infections, EUR 1.5 billion related costs are accrued by healthcare systems in EU/EEA countries [5]. One of the major driving forces behind the acquisition and spread of AMR is the indiscriminate use of antimicrobial agents [6,7]. This exerts ecological pressure on bacteria and contributes to the emergence and selection of multidrug resistance genes which are easily transmitted between humans and animals [8]. Among the commonly isolated strains, the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) constitute a panel of highly recalcitrant bacteria that have garnered immense interest, given their ability to evade common antimicrobial therapies [9,10]. These pathogens have been identified among the WHO’s priority list drawn up in the bid to fortify research efforts and prioritize new drug molecules that outwit multidrug resistance mechanisms [11,12]. However, of the sixty antibiotics and biologics under Pharmaceutics 2020, 12, 643; doi:10.3390/pharmaceutics12070643 www.mdpi.com/journal/pharmaceutics Pharmaceutics 2020, 12, 643 2 of 25 Pharmaceutics 2020, 12, x 2 of 26 clinicalsixty antibiotics development and (Figurebiologics1), under limited clinical benefit development over existing treatments(Figure 1), haslimited been benefit identified, over and existing very fewtreatments of them has target been the identified, most critical and very gram-negative few of them pathogens target the [ 13most,14]. critical With agram-negative weak antibiotic pathogens pipeline caused[13,14]. byWith the a long weak development antibiotic timelinepipeline ofcaused pre-clinical by the candidates, long development declining timeline private investment of pre-clinical and thecandidates, lack of innovation declining private in developing investment new and antimicrobial the lack of therapies,innovation new in developing approaches new are antimicrobial warranted to etherapies,ffectively new combat approaches drug resistant are warranted infections to [ 15effectively]. combat drug resistant infections [15]. Figure 1. (A) Total numbernumber ofof antimicrobialantimicrobial agentsagents inin clinicalclinical developmentdevelopment [[13].13]. (B) Percentages of specificspecific antibiotic classes in clinical development (inconclusive(inconclusive refers to agents classifiedclassified as having inconclusive data or no agreementagreement among the advisoryadvisory group) [[13]13].. The image is drawn using data from [[13].13]. Engineered nanocarriers represent a growing area of interest for the delivery of antimicrobial cargos [16[16].]. These These platforms platforms have have been been shown shown to address to address the inherent the toxicity,inherent high toxicity, dosage requirementshigh dosage (forrequirements intracellular (for infections intracellular and infections resistant pathogens), and resistant rapid pathogens),in vivo degradation rapid in vivo and degradation short half-lives and (e.g.,short peptide-basedhalf-lives (e.g., therapeutics)peptide-based of therapeutics) antimicrobials of antimicrobials [17]. Efficient delivery[17]. Efficient of drugs delivery to the of infectiondrugs to sitethe atinfection a controllable site at frequencya controllable and dosage frequency have and also dosage been demonstrated have also been [18,19 demonstrated]. Additionally, [18,19]. given theAdditionally, role of commensals given the role in maintaining of commensals homeostasis in maintaining and the homeostasis effect of sub-lethal and the effect antibiotics of sub-lethal on the microbiome,antibiotics on these the microbiome, nanocarriers these are a nanocarriers promising solution are a promising that can solution enhance that pathogen can enhance targeting pathogen [20,21]. Atargeting myriad [20,21]. of lipid A based myriad (e.g., of lipid liposomes, based (e.g., micelles), liposomes, metallic micelles), (e.g., gold metallic nanoparticles) (e.g., gold andnanoparticles) polymeric nanocarriersand polymeric (e.g., nanocarriers nanogels) have (e.g., been nanogels) developed have as delivery been systemsdeveloped for antimicrobialas delivery drugssystems [22 –25for]. Whileantimicrobial lipid-based drugs carriers [22–25]. such While as liposomes lipid-based comprise carriers the such most as well-known liposomes comprise and widely the investigated most well- platform,known and they widely are investigated challenged byplatform, vesicle they instability, are challenged low entrapment by vesicle einstability,fficiency and low sterilizationentrapment diefficiencyfficulties and [16 sterilization]. Moreover, difficulties conventional [16]. Moreover, liposomal conventional vesicles undergo liposomal rapid vesicles elimination undergo from rapid the bloodelimination stream from and the have blood poor stream cell specificity and have [26 poor]. Additionally, cell specificity overcoming [26]. Additionally, the bacteria overcoming cell envelope the isbacteria a major cell obstacle envelope for is liposomal a major obstacle formulations for liposomal and for formulations non-fusogenic and liposomes, for non-fusogenic local extracellular liposomes, releaselocal extracellular [27] can compound release [27] toxic can eff ects.compound On the othertoxic effects. hand, metallic On the nanoparticlesother hand, metallic are limited nanoparticles by toxicity concernsare limited (e.g., by nakedtoxicity iron concerns oxide nanoparticles) (e.g., naked iron and aggregationoxide nanoparticles) issues (e.g., and silver aggregation nanoparticles) issues [28 (e.g.,,29]. Similarly,thesilver nanoparticles) chemical composition[28,29]. Similarly, of polymeric the chemical nanoparticles, composition physicochemical of polymeric properties nanoparticles, (e.g., surface potential)physicochemical and/or theirproperties subsequent (e.g., surface degradation potential) products and/or have their also subsequent been associated degradation with cell products toxicity, stresshave also and inflammatorybeen associated responses with cell [30 toxicity,–32]. Recent stress strategies and inflammatory to uncover advancedresponses delivery [30–32]. systems Recent withstrategies improved to uncover physicochemical advanced delivery properties system ands antibacterialwith improved effects physicochemical include the development properties and of nucleicantibacterial acid nanocarrierseffects include and the their development conjugates. of These nucleic nanocarriers acid nanocarriers possess and excellent their conjugates. biocompatibility, These biodegradabilitynanocarriers possess and targetingexcellent propertiesbiocompatibility, [18]. For bi instance,odegradability aptamer-based and targeting systems properties have been [18]. shown For toinstance, be efficient aptamer-based as promising systems tools againsthave been bacterial shown biofilms, to be efficient possess as excellentpromising antimicrobial tools against activities,bacterial inhibitbiofilms, immune possess cell excellent invasion antimicrobial and
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