Nanotechnology-Based Drug Delivery Systems to Control Bacterial-Biofilm-Associated Lung Infections

Abstract

Airway mucus dysfunction and impaired immunological defenses are hallmarks of several lung diseases, including asthma, cystic fibrosis, and chronic obstructive pulmonary diseases, and are mostly causative factors in bacterial-biofilm-associated respiratory tract infections. Bacteria residing within the biofilm architecture pose a complex challenge in clinical settings due to their increased tolerance to currently available antibiotics and host immune responses, resulting in chronic infections with high recalcitrance and high rates of morbidity and mortality. To address these unmet clinical needs, potential anti-biofilm therapeutic strategies are being developed to effectively control bacterial biofilm. This review focuses on recent advances in the development and application of nanoparticulate drug delivery systems for the treatment of biofilm-associated respiratory tract infections, especially addressing the respiratory barriers of concern for biofilm accessibility and the various types of nanoparticles used to combat biofilms. Understanding the obstacles facing pulmonary drug delivery to bacterial biofilms and nanoparticle-based approaches to combatting biofilm may encourage researchers to explore promising treatment modalities for bacterial-biofilm-associated chronic lung infections.

Keywords: bacterial biofilm; biofilm control; chronic lung infections; mucosal barriers; nanoparticle-based drug delivery.

Figure 3

Diverse antibiotic nanoparticles employed to combat bacterial biofilm. (a) Various antibacterial mechanisms of different nanomaterials; (b) diagram illustrating antibacterial Ag NPs (Ref. [135]); (c) glycoconjugate-based Au NPs developed for targeted treatment against P. aeruginosa biofilm (Ref. [141]), where c1 depicts the essential building blocks for creating of Fuc-AuNP@CAZ and Gal-Au@CAZ, c2 illustrates the one-pot self-assembly procedure and simultaneous integration of Ceftazidime, resulting in Fuc-AuNP@CAZ/Gal-Au@CAZ, and c3 represents the targeted lectin approach of Fuc-AuNP@CAZ/Gal-Au@CAZ, which selectively enters P. aeruginosa to concurrently release the drug and generate heat/ROS when exposed to photoirradiation; (d) mechanisms underlying bacterial damage post exposure to iron NPs (Ref. [151]); (e) a schematic representation of the synthesis of both chitosan NPs and chitosan/rhamnolipid NPs (Ref. [160]); (f) a diagram illustrating the disruption of bacterial biofilm by cationic dextran through the phase transition (Ref. [165]); (g) schematic representation of the preparation of Lipid@PLL-PS NPs and Lipid@DOTAP-PS NPs using the electrostatically driven layer-by-layer method (Ref. [156]).

Figure 4

Strategies for biofilm disruption and dispersion to enhance biofilm eradication. (a) Schematic overview of the approaches for biofilm disruption and dispersion; (b) schematic representation of the preparation of DNase I-loaded MSN-Ag NPs and their role in biofilm eradication (Ref. [183]); (c) schematic overview of the design of alginate lyase-fabricated silver nanocomposites for biofilm eradication (Ref. [74]); (d) schematic representing the potential differences in PslG loading between the liposomes and LCNP formulations (Ref. [187]); (e) overview of quorum sensing circuits in P. aeruginosa: large arrows depict primary regulatory pathways between circuits. Solid arrowheads signify positive regulation; flat, red arrowheads denote negative regulation (Ref. [193]).

Figure 5

Bacterial biofilm dispersion mediated by the c-di-GMP pathway and the design of nanoparticles containing NO donors to facilitate biofilm dispersion through this pathway. (a) Schematic illustration of the role of c-di-GMP signaling molecules in the biofilm lifecycle (adapted with permission from Ref. [179]); (b) schematic illustration of the preparation of gentamicin–NONOate NPs via RAFT polymerization (reprinted with permission from Ref. [208]).

Figure 6

The fabrication strategies of nanoparticles to enhance anti-biofilm efficacy. (a) Schematic illustration of strategies to overcome airway mucus and biofilm matrix barriers; (b) impact of PEG density on biodegradable NPs transport in mucus and their in vivo distribution (Ref. [30]); (c) virous surface modifications of PLGA NPs to investigate their influence on mucus penetrating and cellular uptake (Ref. [218]); (d) illustrative overview of functionalized LNPs combined with moxifloxacin as an innovative therapeutic strategy to eradicate bacterial biofilm (Ref. [223]); (e) change in chemical structure of DA fabricated PEG-block-polylysine (PEG-b-Plys) in acidic pH, and the self-assembly of azithromycin-DA NPs at pH 7.4, followed by release of secondary AZM-PAMAM NPs in the acidic bacterial biofilm microenvironment (Ref. [103]); (f) schematic depiction of the composition of dextran-coated stimuli-responsive NPs and their antibacterial mechanisms activated by low pH and high ROS at the biofilm sites (Ref. [238]).

Figure 7

In vitro and in vivo biofilm models for simulating chronic lung infections. (a) Schematic representation of static bacterial biofilm construction on plastic (Ref. [240]); (b) schematic overview of dynamic bacterial biofilm creation using a flow cell setup (Ref. [242]); (c) outline of the protocol for ex vivo infectious lung model using porcine lung (Ref. [244] with modification); (d) schematic depiction of the human lung-on-chip microsystem (Ref. [248]); (e) timeline detailing the construction of chronic P. aeruginosa lung infections in mice and subsequent interventions (Ref. [103]); (f) diagram illustrating pharmacodynamic experiments in biofilm-infected rat model (Ref. [35]).

Figure 1

Biofilm formation in pathological lung conditions. (a) Schematic illustration of airway mucus alteration under pathological conditions, including asthma, COPD, and CF, which can promote bacteria colonization and growth in the lungs. (b) Schematic illustration of the lifecycle of bacterial biofilm. Planktonic bacteria first adhere to the substratum by flagella and hyphae, after which bacteria begin to divide and produce EPS, which provides a substrate for bacterial growth to form a microcolony. Bacterial microcolonies continue to mature and thicken, forming a bacterial biofilm with a certain three-dimensional structure. Upon bacterial biofilm maturation, bacteria disperse from the biofilm and seek new attachment sites to start a new biofilm cycle.

Figure 2

Mechanisms underlying antibiotic tolerance in bacterial biofilm. (a) The biofilm acts as a barrier and prevents the penetration of antibiotics through diffusion restriction and adhesion. (b) Within biofilms, the presence of persistent bacteria is heightened due to limited nutrient availability. (c) Bacteria within biofilms express specific genes that enhance their resistance to antibiotics.