(337bj) Nanomaterials for Infectious Disease Treatment

Nanomedicines; Nanomaterials; Thin Film; Drug Delivery; Infectious Diseases; Formulations; Liposome; Protein; Injectable Hydrogel; Antibacterial/Antiviral/Antifouling/Antibiofilm Research; Antimicrobial Resistance; Material Science

Abstract:

Infectious diseases caused by various organisms pose a significant threat to human health, with bacteria and viruses accounting for notable proportions. The decline in the discovery and development of new antibiotics, coupled with the emergence of drug-resistant pathogens, has led to a crisis of antimicrobial resistance. While vaccines have played a crucial role in eradicating certain viral pathogens, the effectiveness of vaccination is not guaranteed. With the prediction that infections will regain their lethality, infectious disease treatment remains a pressing challenge, demanding constant innovations at the crossroads of medical, chemical, and physical sciences.

Nanomaterials and nanotechnology have revolutionized drug delivery by offering unique advantages over traditional approaches. Nanomaterials, such as nanoparticles, liposomes, and nanocapsules, are engineered at the nanoscale to enhance drug stability, solubility, targeting, and controlled release. Inspired by natural (biogenic) substances like enzymes and cell membranes, nanomaterials have been combined with biomimetic properties to enable antimicrobial effects as a potential solution to the issue of drug resistance. Bio-inspired nanomaterials have been developed to target drug delivery, enable sustained release, cross biological barriers, and enhance efficacy. We have developed some of the biomimetic nanomaterials to encapsulate existing therapeutics (e.g., to achieve local drug delivery), while others serve as therapeutics to combat infectious diseases, especially those with drug resistance.

In the context of otitis media, a common middle ear infection in children that often leads to oral antibiotic usage and the risk of antibiotic resistance, we have developed polyvinylpyrrolidone-coated silver nanoparticles (AgNPs-PVP) with potent antimicrobial properties. These nanoparticles completely eliminated Streptococcus pneumoniae (S. pneumoniae) and nontypeable Haemophilus influenzae (NTHi), the common pathogens associated with otitis media, at concentrations of 1.04 and 2.13 μg/ml, respectively. The superior antimicrobial effectiveness against S. pneumoniae was attributed to its H₂O₂-producing ability, which synergistically interacted with AgNPs. To enable sustained local delivery of AgNPs-PVP, a hydrogel formulation of 18% P407 was developed. This hydrogel-based system could be injected through perforated tympanic membranes, rapidly gelling upon entering the warm auditory bullae and providing sustained release of antimicrobials. The hydrogel-based local delivery system eradicated otitis media pathogens without cytotoxicity, offering a promising alternative to conventional antibiotics.

Additionally, a local treatment strategy was designed to convert the metabolic product H₂O₂ of S. pneumoniae into a potent antiseptic, HOBr, through the catalytic activity of locally administered vanadium pentoxide nanowires (V₂O₅ NWs) with Br^-. This strategy is based on V₂O₅ NWs‘s ability to mimic natural enzyme, haloperoxidase (HPO), in seaweed. This on-demand generation of therapeutics for otitis media treatment effectively eradicated the S. pneumoniae induced infection without tissue toxicity or negative effects on hearing sensitivity in a chinchilla model.

Furthermore, to treat another major pathogen in otitis media, NTHi, which does not produce H₂O₂, a cascade nanozyme has been designed to generate HOBr from O₂. The cascade nanozyme simultaneously exhibited glucose oxidase (GOx)-like activity, from AuNPs, and HPO-mimicking activity, from V₂O₅ NWs, connected using dopamine (DPA). The cascade nanozyme successfully eradicated NTHi in vitro in 24 hours. This material-oriented infectious disease treatment strategy enables the real-time generation of small-molecule antimicrobials at the infection site, potentially reducing the development of antimicrobial resistance and minimizing side effects.

Moreover, the local delivery of antibiotics to the middle ear requires crossing the tympanic membrane (TM), which is minimally permeable to nearly all molecules. We developed a fresh concept that leveraged the innate immune response to achieve an unprecedented transtympanic delivery efficiency and complete eradication of OM in vivo. This design harnessed neutrophils as endogenous micromotors for the targeted delivery of the antimicrobial cargo to the infected middle ear. The neutrophil hitchhiking was enabled by a simple liposome, which was designed to trigger enhanced opsonization by complement proteins and subsequently phagocytosis by neutrophils. This delivery strategy achieved an unprecedented transtympanic delivery ratio that is two-orders-of-magnitude greater than existing liposome-free systems. The formulation eradicates OM in 100% of the chinchillas infected by NTHi. The strategy of leveraging the complement system to harness neutrophils was unprecedented, which bypassed the need for costly targeting biomolecules for the treatment of this prevalent disease, thus accelerating the progression along the discovery to deployment pathway to reduce pediatric antibiotic usage globally.

Bacterial coinfections, like middle ear infections, involve multiple species and present diagnostic and treatment challenges. Identifying specific strains and their antibiotic susceptibility is time-consuming. Careful antibiotic use is necessary to prevent resistance. In middle ear infections, S. pneumoniae and NTHi are commonly found together, with NTHi promoting S. pneumoniae biofilm formation. We used V₂O₅ NWs nanozymes to treat coinfection in a chinchilla model, utilizing S. pneumoniae product as a substrate. S. pneumoniae supplied H₂O₂ for nanozyme activity, producing antimicrobial HOBr when co-cultured with NTHi. Both bacteria were inhibited at 0.64 mg/ml of V₂O₅ NWs.

Taking the coronavirus as an example, we have examined the antiviral efficacy of CeO_2-x nanorods that mimic HPO as well. Nanorods with an aspect ratio of 4.5 demonstrated remarkable antiviral properties against the human coronavirus OC43. These nanorods acted as catalysts, facilitating the oxidative bromination of Br^- and H₂O₂ to produce HOBr, leading to a significant reduction in the infection rate of the OC43 virus in HCT-8 cells. The infection rate reduced from 55.3% to 6.1% after a brief 15-minute incubation with the nanorods. These findings underscore the tremendous potential of this catalytic system as an effective solution for combating viral infections.