This review focuses on the development of nanoparticle systems for antimicrobial drug delivery. Numerous antimicrobial drugs have been prescribed to kill or inhibit the growth of microbes such as bacteria, fungi and viruses. Even though the therapeutic efficacy of these drugs has been well established, inefficient delivery could result in inadequate therapeutic index and local and systemic side effects including cutaneous irritation, peeling, scaling and gut flora reduction. Nanostructured biomaterials, nanoparticles in particular, have unique physicochemical properties such as ultra small and controllable size, large surface area to mass ratio, high reactivity, and functionalizable structure. These properties can be applied to facilitate the administration of antimicrobial drugs, thereby overcoming some of the limitations in traditional antimicrobial therapeutics. In recent years, encapsulation of antimicrobial drugs in nanoparticle systems has emerged as an innovative and promising alternative that enhances therapeutic effectiveness and minimizes undesirable side effects of the drugs. Here the current progress and challenges in synthesizing nanoparticle platforms for delivering various antimicrobial drugs are reviewed. We also call attention to the need to unite the shared interest between nanoengineers and microbiologists in developing nanotechnology for the treatment of microbial diseases.

We report a new approach to selectively delivering antimicrobials to the sites of bacterial infections by utilizing bacterial toxins to activate drug release from gold nanoparticle-stabilized phospholipid liposomes. The binding of chitosan modified gold nanoparticles to the surface of liposomes can effectively prevent them from fusing with one another and from undesirable payload release in regular storage or physiological environments. However, once these protected liposomes "see" bacteria that secrete toxins, the toxins will insert into the liposome membranes and form pores, through which the encapsulated therapeutic agents are released. The released drugs subsequently impose antimicrobial effects on the toxin-secreting bacteria. Using methicillinresistant Staphycoccus aureus (MRSA) as a model bacterium and vacomycin as a model anti-MRSA antibiotic, we demonstrate that the synthesized gold nanoparticle-stabilized liposomes can completely release the encapsulated vacomycin within 24 h in the presence of MRSA bacteria and lead to inhibition of MRSA growth as effective as an equal amount of vacomycin loaded liposomes (without nanoparticle stabilizers) and free vacomycin. This bacterial toxin enabled drug release from nanoparticle-stabilized liposomes provides a new, safe and effective approach for the treatment of bacterial infections. This technique can be broadly applied to treat a variety of infections caused by bacteria that secrete pore-forming toxins.

This study evaluated the antimicrobial activity of lauric acid (LA) and its liposomal derivatives against Propionibacterium acnes (P. acnes), the bacterium that promotes inflammatory acne. First, the antimicrobial study of three free fatty acids (lauric acid, palmitic acid and oleic acid) demonstrated that LA gives the strongest bactericidal activity against P. acnes. However, a setback of using LA as a potential treatment for inflammatory acne is its poor water solubility. Then the LA was incorporated into a liposome formulation to aid its delivery to P. acnes. It's demonstrated that the antimicrobial activity of LA was not only well maintained in its liposomal derivatives but also enhanced at low LA concentration. In addition, the antimicrobial activity of LA-loaded liposomes (LipoLA) mainly depended on the LA loading concentration per single liposomes. Further study found that the LipoLA could fuse with the membranes of P. acnes and release the carried LA directly into the bacterial membranes, thereby killing the bacteria effectively. Since LA is a natural compound that is the main acid in coconut oil and also resides in human breast milk and liposomes have been successfully and widely applied as a drug delivery vehicle in the clinic, the LipoLA developed in this work holds great potential of becoming an innate, safe and effective therapeutic medication for acne vulgaris and other P. acnes associated diseases.

We report a new approach to control the fusion activity of liposomes by adsorbing carboxyl-modified gold nanoparticles to the outer surface of phospholipid liposomes. The bound gold nanoparticles can effectively prevent liposomes from fusing with one another at neutral pH value, while at acidic environments (e.g. pH<5), the gold particle stabilizers will detach from the liposomes, with liposome fusion activity resuming. The binding of carboxyl-modified gold nanoparticles to cationic phospholipid liposomes at neutral pH and detaching at acidic pH values are evaluated and confirmed by dynamic light scattering, electron microscopy, fluorescence and UV-vis absorption experiments. The relative fusion efficiency of gold nanoparticle-stabilized cationic liposomes with anionic liposomes is ~25% at pH=7 in contrast to ~80% at pH=4. Since liposomes have been extensively used as drug nanocarriers and the infectious lesions on human skin are typically acidic with a pH<5, these acid-responsive liposomes with tunable fusion ability hold great promise for dermal drug delivery to treat a variety of skin diseases such as acne vulgaris and staph infections.

Staphylococcus aureus (S. aureus) represents a major threat to a broad range of healthcare and community associated infections. This bacterium has rapidly evolved resistance to multiple drugs throughout its antibiotic history and thus it is imperative to develop novel antimicrobial strategies to enrich the currently shrinking therapeutic options against S. aureus. This study evaluated the antimicrobial activity and therapeutic efficacy of oleic acid (OA) in a liposomal formulation as an innate bactericide against methicillin-resistant S. aureus (MRSA). In vitro studies showed that these OA-loaded liposomes (LipoOA) could rapidly fuse into the bacterial membranes, thereby significantly improving the potency of OA to kill MRSA compared with the use of free OA. Further in vivo tests demonstrated that LipoOA were highly effective in curing skin infections caused by MRSA bacteria and preserving the integrity of the infected skin using a mouse skin model. Moreover, a preliminary skin toxicity study proved high biocompatibility of LipoOA to normal skin tissues. These findings suggest that LipoOA hold great potential to become a new, effective, and safe antimicrobial agent for the treatment of MRSA infections.