Construction of disulfide containing redox-responsive polymeric nanomedicine.

Disulfide bonds (S-S) are widely found in chemistry, biology, and materials science. Polymer nanomaterials containing disulfide bonds with a variety of excellent properties have great potential as drug and gene delivery carriers. The disulfide bond can exist stably in extracellular environment, but upon entering cancer cells, it will undergo a sulfhydryl-disulfide bond exchange reaction with glutathione (GSH) in the cytoplasm, causing the disulfide bond cleavage. Therefore, polymeric nanomaterials containing disulfide bonds are promising in cancer treatment due to the elevated GSH concentration inside cancer cells. This review highlights various synthetic approaches to prepare disulfide containing redox-responsive polymeric nanomedicine, including synthesis of disulfide bonds containing polymers, construction of polymeric nanoparticle with shell or core crosslinked disulfide bonds, preparation of polymer-drug conjugates via disulfide linkers, and disulfide linked responsive payloads.

Morphologic Design of Silver-Bearing Sugar-Based Polymer Nanoparticles for Uroepithelial Cell Binding and Antimicrobial Delivery.

Platelet-like and cylindrical nanostructures from sugar-based polymers are designed to mimic the aspect ratio of bacteria and achieve uroepithelial cell binding and internalization, thereby improving their potential for local treatment of recurrent urinary tract infections. Polymer nanostructures, derived from amphiphilic block polymers composed of zwitterionic poly(d-glucose carbonate) and semicrystalline poly(l-lactide) segments, were constructed with morphologies that could be tuned to enhance uroepithelial cell binding. These nanoparticles exhibited negligible cytotoxicity, immunotoxicity, and cytokine adsorption, while also offering substantial silver cation loading capacity, extended release, and in vitro antimicrobial activity (as effective as free silver cations) against uropathogenic Escherichia coli. In comparison to spherical analogues, cylindrical and platelet-like nanostructures engaged in significantly higher association with uroepithelial cells, as measured by flow cytometry; despite their larger size, platelet-like nanostructures maintained the capacity for cell internalization. This work establishes initial evidence of degradable platelet-shaped nanostructures as versatile therapeutic carriers for treatment of epithelial infections.

In Situ Production of Ag/Polymer Asymmetric Nanoparticles via a Powerful Light-Driven Technique.

As a rapid, controllable, and easily transferrable approach to the preparation of antimicrobial nanoparticle systems, a one-step, light-driven procedure was developed to produce asymmetric hybrid inorganic-organic nanoparticles (NPs) directly from a homogeneous Ag/polymer mixture. An amphiphilic triblock polymer was designed and synthesized to build biocompatible NPs, consisting of poly(ethylene oxide) (PEO), carboxylic acid-functionalized polyphosphoester (PPE), and poly(l-lactide) (PLLA). Unexpectedly, snowman-like asymmetric nanostructures were subsequently obtained by simply loading silver cations into the polymeric micelles together with purification via centrifugation. With an understanding of the chemistry of the asymmetric NP formation, a controllable preparation strategy was developed by applying UV irradiation. A morphology transition was observed by transmission electron microscopy over the UV irradiation time, from small silver NPs distributed inside the micelles into snowman-like asymmetric NPs, which hold promise for potential antimicrobial applications with their unique two-stage silver release profiles.

Polymeric Nanoparticles with a Glutathione-Sensitive Heterodimeric Multifunctional Prodrug for In Vivo Drug Monitoring and Synergistic Cancer Therapy.

Polymeric micelle-based drug delivery systems have dramatically improved the delivery of small molecular drugs, yet multiple challenges remain to be overcome. A polymeric nanomedicine has now been engineered that possesses an ultrahigh loading (59 %) of a glutathione (GSH)-sensitive heterodimeric multifunctional prodrug (HDMP) to effectively co-deliver two synergistic drugs to tumors. An HDMP comprising of chemotherapeutic camptothecin (CPT) and photosensitizer 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-α (HPPH) was conjugated via a GSH-cleavable linkage. The intrinsic fluorogenicity and label-free radio-chelation (64 Cu) of HPPH enabled direct drug monitoring by fluorescence imaging and positron emission tomography (PET). Through quantitative PET imaging, HDMP significantly improves drug delivery to tumors. The high synergistic therapeutic efficacy of HDMP-loaded NPs highlights the rational design of HDMP, and presents exciting opportunities for polymer NP-based drug delivery.

Double-Layered Plasmonic-Magnetic Vesicles by Self-Assembly of Janus Amphiphilic Gold-Iron(II,III) Oxide Nanoparticles.

Janus nanoparticles (JNPs) offer unique features, including the precisely controlled distribution of compositions, surface charges, dipole moments, modular and combined functionalities, which enable excellent applications that are unavailable to their symmetrical counterparts. Assemblies of NPs exhibit coupled optical, electronic and magnetic properties that are different from single NPs. Herein, we report a new class of double-layered plasmonic-magnetic vesicle assembled from Janus amphiphilic Au-Fe3 O4 NPs grafted with polymer brushes of different hydrophilicity on Au and Fe3 O4 surfaces separately. Like liposomes, the vesicle shell is composed of two layers of Au-Fe3 O4 NPs in opposite direction, and the orientation of Au or Fe3 O4 in the shell can be well controlled by exploiting the amphiphilic property of the two types of polymers.

Improving paclitaxel delivery: in vitro and in vivo characterization of PEGylated polyphosphoester-based nanocarriers.

Nanomaterials have great potential to offer effective treatment against devastating diseases by providing sustained release of high concentrations of therapeutic agents locally, especially when the route of administration allows for direct access to the diseased tissues. Biodegradable polyphosphoester-based polymeric micelles and shell cross-linked knedel-like nanoparticles (SCKs) have been designed from amphiphilic block-graft terpolymers, PEBP-b-PBYP-g-PEG, which effectively incorporate high concentrations of paclitaxel (PTX). Well-dispersed nanoparticles physically loaded with PTX were prepared, exhibiting desirable physiochemical characteristics. Encapsulation of 10 wt% PTX, into either micelles or SCKs, allowed for aqueous suspension of PTX at concentrations up to 4.8 mg/mL, as compared to <2.0 µg/mL for the aqueous solubility of the drug alone. Drug release studies indicated that PTX released from these nanostructures was defined through a structure-function relationship, whereby the half-life of sustained PTX release was doubled through cross-linking of the micellar structure to form SCKs. In vitro, physically loaded micellar and SCK nanotherapeutics demonstrated IC50 values against osteosarcoma cell lines, known to metastasize to the lungs (CCH-OS-O and SJSA), similar to the pharmaceutical Taxol formulation. Evaluation of these materials in vivo has provided an understanding of the effects of nanoparticle structure-function relationships on intratracheal delivery and related biodistribution and pharmacokinetics. Overall, we have demonstrated the potential of these novel nanotherapeutics toward future sustained release treatments via administration directly to the sites of lung metastases of osteosarcoma.

Holistic assessment of covalently labeled core-shell polymeric nanoparticles with fluorescent contrast agents for theranostic applications.

The successful development of degradable polymeric nanostructures as optical probes for use in nanotheranostic applications requires the intelligent design of materials such that their surface response, degradation, drug delivery, and imaging properties are all optimized. In the case of imaging, optimization must result in materials that allow differentiation between unbound optical contrast agents and labeled polymeric materials as they undergo degradation. In this study, we have shown that use of traditional electrophoretic gel-plate assays for the determination of the purity of dye-conjugated degradable nanoparticles is limited by polymer degradation characteristics. To overcome these limitations, we have outlined a holistic approach to evaluating dye and peptide-polymer nanoparticle conjugation by utilizing steady-state fluorescence, anisotropy, and emission and anisotropy lifetime decay profiles, through which nanoparticle-dye binding can be assessed independently of perturbations, such as those presented during the execution of electrolyte gel-based assays. This approach has been demonstrated to provide an overall understanding of the spectral signature-structure-function relationship, ascertaining key information on interactions between the fluorophore, polymer, and solvent components that have a direct and measurable impact on the emissive properties of the optical probe. The use of these powerful techniques provides feedback that can be utilized to improve nanotheranostics by evaluating dye emissivity in degradable nanotheranostic systems, which has become increasingly important as modern platforms transition to architectures intentionally reliant on degradation and built-in environmental responses.

Rapid and versatile construction of diverse and functional nanostructures derived from a polyphosphoester-based biomimetic block copolymer system.

A rapid and efficient approach for the preparation and modification of a versatile class of functional polymer nanoparticles has been developed, for which the entire engineering process from small molecules to polymers to nanoparticles bypasses typical slow and inefficient procedures and rather employs a series of steps that capture fully the "click" chemistry concepts that have greatly facilitated the preparation of complex polymer materials over the past decade. The construction of various nanoparticles with functional complexity from a versatile platform is a challenging aim to provide materials for fundamental studies and also optimization toward a diverse range of applications. In this paper, we demonstrate the rapid and facile preparation of a family of nanoparticles with different surface charges and functionalities based on a biodegradable polyphosphoester block copolymer system. From a retrosynthetic point of view, the nonionic, anionic, cationic, and zwitterionic micelles with hydrodynamic diameters between 13 and 21 nm and great size uniformity were quickly formed by suspending, independently, four amphiphilic diblock polyphosphoesters into water, which were functionalized from the same parental hydrophobic-functional AB diblock polyphosphoester by click-type thiol-yne reactions. The well-defined (PDI < 1.2) hydrophobic-functional AB diblock polyphosphoester was synthesized by an ultrafast (<5 min) organocatalyzed ring-opening polymerization in a two-step, one-pot manner with the quantitative conversions of two kinds of cyclic phospholane monomers. The whole programmable process starting from small molecules to nanoparticles could be completed within 6 h, as the most rapid approach for the anionic and nonionic nanoparticles, although the cationic and zwitterionic nanoparticles required ca. 2 days due to purification by dialysis. The micelles showed high biocompatibility, with even the cationic micelles exhibiting a 6-fold lower cytotoxicity toward RAW 264.7 mouse macrophage cells, as compared to the commercial transfection agent Lipofectamine.

Advances in the polymeric delivery of nucleic acid vaccines.

Nucleic acid vaccines, especially messenger RNA (mRNA) vaccines, display unique benefits in the current COVID-19 pandemic. The application of polymeric materials as delivery carriers has greatly promoted nucleic acid vaccine as a promising prophylactic and therapeutic strategy. The inherent properties of polymeric materials render nucleic acid vaccines with excellent in vivo stability, enhanced biosafety, specific cellular uptake, endolysosomal escape, and promoted antigen expression. Although polymeric delivery of nucleic acid vaccines has progressed significantly in the past decades, clinical translation of polymer-gene vaccine systems still faces insurmountable challenges. This review summarizes the diverse polymers and their characterizations and representative formulations for nucleic acid vaccine delivery. We also discussed existing problems, coping strategies, and prospect relevant to applications of nucleic acid vaccines and polymeric carriers. This review highlights the rational design and development of polymeric vaccine delivery systems towards meeting the goals of defending serious or emerging diseases.

Responsive Multivesicular Polymeric Nanovaccines that Codeliver STING Agonists and Neoantigens for Combination Tumor Immunotherapy.

Immune checkpoint blockade (ICB) has significantly advanced cancer immunotherapy, yet its patient response rates are generally low. Vaccines, including immunostimulant-adjuvanted peptide antigens, can improve ICB. The emerging neoantigens generated by cancer somatic mutations elicit cancer-specific immunity for personalized immunotherapy; the novel cyclic dinucleotide (CDN) adjuvants activate stimulator of interferon genes (STING) for antitumor type I interferon (IFN-I) responses. However, CDN/neoantigen vaccine development has been limited by the poor antigen/adjuvant codelivery. Here, pH-responsive CDN/neoantigen codelivering nanovaccines (NVs) for ICB combination tumor immunotherapy are reported. pH-responsive polymers are synthesized to be self-assembled into multivesicular nanoparticles (NPs) at physiological pH and disassembled at acidic conditions. NPs with high CDN/antigen coloading are selected as NVs for CDN/antigen codelivery to antigen presenting cells (APCs) in immunomodulatory lymph nodes (LNs). In the acidic endosome of APCs, pH-responsive NVs facilitate the vaccine release and escape into cytosol, where CDNs activate STING for IFN-I responses and antigens are presented by major histocompatibility complex (MHC) for T-cell priming. In mice, NVs elicit potent antigen-specific CD8+ T-cell responses with immune memory, and reduce multifaceted tumor immunosuppression. In syngeneic murine tumors, NVs show robust ICB combination therapeutic efficacy. Overall, these CDN/neoantigen-codelivering NVs hold the potential for ICB combination tumor immunotherapy.

Smart Nanovesicle-Mediated Immunogenic Cell Death through Tumor Microenvironment Modulation for Effective Photodynamic Immunotherapy.

Combination therapy that could better balance immune activation and suppressive signals holds great potential in cancer immunotherapy. Herein, we serendipitously found that the pH-responsive nanovesicles (pRNVs) self-assembled from block copolymer polyethylene glycol-b-cationic polypeptide can not only serve as a nanocarrier but also cause immunogenic cell death (ICD) through preapoptotic exposure of calreticulin. After coencapsulation of a photosensitizer, 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH) and an indoleamine 2,3-dioxygenase inhibitor, indoximod (IND), pRNVs/HPPH/IND at a single low dose elicited significant antitumor efficacy and abscopal effect following laser irradiation in a B16F10 melanoma tumor model. Treatment efficacy attributes to three key factors: (i) singlet oxygen generation by HPPH-mediated photodynamic therapy (PDT); (ii) increased dendritic cell (DC) recruitment and immune response provocation after ICD induced by pRNVs and PDT; and (iii) tumor microenvironment modulation by IND via enhancing P-S6K phosphorylation for CD8+ T cell development. This study exploited the nanocarrier to induce ICD for the host's immunity activation. The "all-in-one" smart nanovesicles allow the design of multifunctional materials to strengthen cancer immunotherapy efficacy.

Zwitterionic-to-cationic charge conversion polyprodrug nanomedicine for enhanced drug delivery.

Zwitterionic surface modification is a promising strategy for nanomedicines to achieve prolonged circulation time and thus effective tumor accumulation. However, zwitterion modified nanoparticles suffer from reduced cellular internalization efficiency. Methods: A polyprodrug-based nanomedicine with zwitterionic-to-cationic charge conversion ability (denoted as ZTC-NMs) was developed for enhanced chemotherapeutic drug delivery. The polyprodrug consists of pH-responsive poly(carboxybetaine)-like zwitterionic segment and glutathione-responsive camptothecin prodrug segment. Results: The ZTC-NMs combine the advantages of zwitterionic surface and polyprodrug. Compared with conventional zwitterionic surface, the ZTC-NMs can respond to tumor microenvironment and realize ZTC surface charge conversion, thus improve cellular internalization efficiency of the nanomedicines. Conclusions: This ZTC method offers a strategy to promote the drug delivery efficiency and therapeutic efficacy, which is promising for the development of cancer nanomedicines.

In Situ shRNA Synthesis on DNA-Polylactide Nanoparticles to Treat Multidrug Resistant Breast Cancer.

Nanomedicine has shown unprecedented potential for cancer theranostics. Nucleic acid (e.g., DNA and RNA) nanomedicines are of particular interest for combination therapy with chemotherapeutics. However, current nanotechnologies to construct such nucleic acid nanomedicines, which rely on chemical conjugation or physical complexation of nucleic acids with chemotherapeutics, have restrained their clinical translation due to limitations such as low drug loading efficiency and poor biostability. Herein, in situ rolling circle transcription (RCT) is applied to synthesize short hairpin RNA (shRNA) on amphiphilic DNA-polylactide (PLA) micelles. Core-shell PLA@poly-shRNA structures that codeliver a high payload of doxorubicin (Dox) and multidrug resistance protein 1 (MDR1) targeted shRNA for MDR breast cancer (BC) therapy are developed. DNA-PLA conjugates are first synthesized, which then self-assemble into amphiphilic DNA-PLA micelles; next, using the conjugated DNA as a promoter, poly-shRNA is synthesized on DNA-PLA micelles via RCT, generating PLA@poly-shRNA microflowers; and finally, microflowers are electrostatically condensed into nanoparticles using biocompatible and multifunctional poly(ethylene glycol)-grafted polypeptides (PPT-g-PEG). These PLA@poly-shRNA@PPT-g-PEG nanoparticles are efficiently delivered into MDR breast cancer cells and accumulated in xenograft tumors, leading to MDR1 silencing, intracellular Dox accumulation, potentiated apoptosis, and enhanced tumor therapeutic efficacy. Overall, this nanomedicine platform is promising to codeliver anticancer nucleic acid therapeutics and chemotherapeutics.

Polyrotaxane-based supramolecular theranostics.

The development of smart theranostic systems with favourable biocompatibility, high loading efficiency, excellent circulation stability, potent anti-tumour activity, and multimodal diagnostic functionalities is of importance for future clinical application. The premature burst release and poor degradation kinetics indicative of polymer-based nanomedicines remain the major obstacles for clinical translation. Herein we prepare theranostic shell-crosslinked nanoparticles (SCNPs) using a ß-cyclodextrin-based polyrotaxane (PDI-PCL-b-PEG-RGD⊃ß-CD-NH2) to avoid premature drug leakage and achieve precisely controllable release, enhancing the maximum tolerated dose of the supramolecular nanomedicines. cRGDfK and perylene diimide are chosen as the stoppers of PDI-PCL-b-PEG-RGD⊃ß-CD-NH2, endowing the resultant SCNPs with excellent integrin targeting ability, photothermal effect, and photoacoustic capability. In vivo anti-tumour studies demonstrate that drug-loaded SCNPs completely eliminate the subcutaneous tumours without recurrence after a single-dose injection combining chemotherapy and photothermal therapy. These supramolecular nanomedicines also exhibit excellent anti-tumour performance against orthotopic breast cancer and prevent lung metastasis with negligible systemic toxicity.

Croconaine nanoparticles with enhanced tumor accumulation for multimodality cancer theranostics.

A novel nanoparticle self-assembled by polyethylene glycol (PEG) modified croconaine dye (CR780) is presented for photoacoustic (PA)/near-infrared (NIR) fluorescence imaging-guided photothermal therapy (PTT). The simple PEGylation made CR780 amphiphilic, and led to their self-assembly into well-defined and uniform nanostructures with size tunable by controlling the assembly conditions. The CR780-PEG5K not only displayed the strength of small molecules (including rapid distribution to different organs, fast renal clearance and minimal accumulation to normal tissues), but also demonstrated the advantages of nanomaterials (including high physiological stability, multimodal theranostic ability, high tumor accumulation and retention). These facilely synthesized molecular nanoprobes showed great clinical translation potential as a versatile theranostic agent.

Self-Assembly of Semiconducting-Plasmonic Gold Nanoparticles with Enhanced Optical Property for Photoacoustic Imaging and Photothermal Therapy.

Although various noble metal and semiconducting molecules have been developed as photoacoustic (PA) agents, the use of semiconducting polymer-metal nanoparticle hybrid materials to enhance PA signal has not been explored. A novel semiconducting-plasmonic nanovesicle was fabricated by self-assembly of semiconducting poly(perylene diimide) (PPDI) and poly(ethylene glycol (PEG) tethered gold nanoparticles (Au@PPDI/PEG). A highly localized and strongly enhanced electromagnetic (EM) field is distributed between adjacent gold nanoparticles in the vesicular shell, where the absorbing collapsed PPDI is present. Significantly, the EM field in turn enhances the light absorption efficiency of PPDI, leading to a much greater photothermal effect and a stronger photoacoustic signal compared to PDI nanoparticle or gold nanovesicle alone. The optical property of the hybrid vesicle can be further tailored by controlling the ratio of PPDI and gold nanoparticle as well as the adjustable interparticle distance of gold nanoparticles localized in the vesicular shell. In vivo imaging and therapeutic evaluation demonstrated that the hybrid vesicle is an excellent probe for cancer theranostics.

Polyphosphoester nanoparticles as biodegradable platform for delivery of multiple drugs and siRNA.

Delivery of multiple therapeutics and/or diagnostic agents to diseased tissues is challenging and necessitates the development of multifunctional platforms. Among the various strategies for design of multifunctional nanocarriers, biodegradable polyphosphoester (PPE) polymers have been recently synthesized via a rapid and simple synthetic strategy. In addition, the chemical structure of the polymer could be tuned to form nanoparticles with varying surface chemistries and charges, which have shown exceptional safety and biocompatibility as compared to several commercial agents. The purpose of this study was to exploit a mixture of PPE nanoparticles of cationic and neutral surface charges for multiple delivery of anticancer drugs (ie, sorafenib and paclitaxel) and nucleic acids (ie, siRNA). Cationic PPE polymers could efficiently complex siRNA, and the stability of the nanoparticles could be maintained in physiological solutions and upon freeze-drying and were able to deliver siRNA in vivo when injected intravenously in mice. Commercially available cationic polyethylenimine polymer had LD50 of ca. 61.7 mg/kg in mice, whereas no animal died after injection of the cationic PPE polymer at a dose of >130 mg/kg. Neutral PPE nanoparticles were able to encapsulate two hydrophobic drugs, namely, sorafenib and paclitaxel, which are commonly used for the treatment of hepatocellular carcinoma. Mixing the neutral and cationic PPE nanoparticles did not result in any precipitation, and the size characteristics of both types of nanoparticles were maintained. Hence, PPE polymers might have potential for the delivery of multiple drugs and diagnostic agents to diseased tissues via simple synthesis of the individual polymers and assembly into nanoparticles that can host several drugs while being mixed in the same administration set, which is of importance for industrial and clinical development.

Light-Responsive Biodegradable Nanomedicine Overcomes Multidrug Resistance via NO-Enhanced Chemosensitization.

Multidrug resistance (MDR) is responsible for the relatively low effectiveness of chemotherapeutics. Herein, a nitric oxide (NO) gas-enhanced chemosensitization strategy is proposed to overcome MDR by construction of a biodegradable nanomedicine formula based on BNN6/DOX coloaded monomethoxy(polyethylene glycol)-poly(lactic-co-glycolic acid) (mPEG-PLGA). On one hand, the nanomedicine features high biocompatibility due to the high density of PEG and biodegradable PLGA. On the other hand, the nanoformula exhibits excellent stability under physiological conditions but exhibits stimuli-responsive decomposition of BNN6 for NO gas release upon ultraviolet-visible irradiation. More importantly, after NO release is triggered, gas molecules are generated that break the nanoparticle shell and lead to the release of doxorubicin. Furthermore, NO was demonstrated to reverse the MDR of tumor cells and enhance the chemosensitization for doxorubicin therapy.

Degradable polyphosphoester-based silver-loaded nanoparticles as therapeutics for bacterial lung infections.

In this study, a new type of degradable polyphosphoester-based polymeric nanoparticle, capable of carrying silver cations via interactions with alkyne groups, has been developed as a potentially effective and safe treatment for lung infections. It was found that up to 15% (w/w) silver loading into the nanoparticles could be achieved, consuming most of the pendant alkyne groups along the backbone, as revealed by Raman spectroscopy. The well-defined Ag-loaded nanoparticles released silver in a controlled and sustained manner over 5 days, and displayed enhanced in vitro antibacterial activities against cystic fibrosis-associated pathogens and decreased cytotoxicity to human bronchial epithelial cells, in comparison to silver acetate.

Preparation and in vitro antimicrobial activity of silver-bearing degradable polymeric nanoparticles of polyphosphoester-block-poly(L-lactide).

The development of well-defined polymeric nanoparticles (NPs) as delivery carriers for antimicrobials targeting human infectious diseases requires rational design of the polymer template, an efficient synthetic approach, and fundamental understanding of the developed NPs, e.g., drug loading/release, particle stability, and other characteristics. Herein, we developed and evaluated the in vitro antimicrobial activity of silver-bearing, fully biodegradable and functional polymeric NPs. A series of degradable polymeric nanoparticles (dNPs), composed of phosphoester and L-lactide and designed specifically for silver loading into the hydrophilic shell and/or the hydrophobic core, were prepared as potential delivery carriers for three different types of silver-based antimicrobials-silver acetate or one of two silver carbene complexes (SCCs). Silver-loading capacities of the dNPs were not influenced by the hydrophilic block chain length, loading site (i.e., core or shell), or type of silver compound, but optimization of the silver feed ratio was crucial to maximize the silver loading capacity of dNPs, up to ca. 12% (w/w). The release kinetics of silver-bearing dNPs revealed 50% release at ca. 2.5-5.5 h depending on the type of silver compound. In addition, we undertook a comprehensive evaluation of the rates of hydrolytic or enzymatic degradability and performed structural characterization of the degradation products. Interestingly, packaging of the SCCs in the dNP-based delivery system improved minimum inhibitory concentrations up to 70%, compared with the SCCs alone, as measured in vitro against 10 contemporary epidemic strains of Staphylococcus aureus and eight uropathogenic strains of Escherichia coli. We conclude that these dNP-based delivery systems may be beneficial for direct epithelial treatment and/or prevention of ubiquitous bacterial infections, including those of the skin and urinary tract.