Efforts to extend nanoparticle residence time in vivo have inspired many strategies in particle surface modifications to bypass macrophage uptake and systemic clearance. Here we report a top-down biomimetic approach in particle functionalization by coating biodegradable polymeric nanoparticles with natural erythrocyte membranes, including both membrane lipids and associated membrane proteins for long-circulating cargo delivery. The structure, size and surface zeta potential, and protein contents of the erythrocyte membrane-coated nanoparticles were verified using transmission electron microscopy, dynamic light scattering, and gel electrophoresis, respectively. Mice injections with fluorophore-loaded nanoparticles revealed superior circulation half-life by the erythrocytemimicking nanoparticles as compared to control particles coated with the state-of-the-art synthetic stealth materials. Biodistribution study revealed significant particle retention in the blood 72 h following the particle injection. The translocation of natural cellular membranes, their associated proteins, and the corresponding functionalities to the surface of synthetic particles represents a unique approach in nanoparticle functionalization.biomimetic nanoparticle | drug delivery | long circulation | red blood cell membrane

Combination chemotherapy and nanoparticle drug delivery are two areas that have shown significant promise in cancer treatment. Combined therapy of two or more drugs promotes synergism among the different drugs against cancer cells and suppresses drug resistance through distinct mechanisms of action. Nanoparticle drug delivery, on the other hand, enhances therapeutic effectiveness and reduces side effects of the drug payloads by improving their pharmacokinetics. These two active research fields have been recently merged to further improve the efficacy of cancer therapeutics. This review article summarizes the recent efforts in developing nanoparticle platforms to concurrently deliver multiple types of drugs for combination chemotherapy. We also highlight the challenges and design specifications that need to be considered in optimizing nanoparticle-based combination chemotherapy.

We report the synthesis of novel acid-responsive therapeutic nanoparticles (NPs) with sub-100 nm size consisting of polymer-cisplatin conjugates. The uniqueness of these drug delivery polymeric NPs lies in the covalent conjugation of each cisplatin drug to the hydrophobic segment of two biocompatible diblock copolymer chains through hydrazone bond, resulting in highly differential drug release profile at different environmental acidity. We demonstrate that the synthesized polymercisplatin conjugates can readily precipitate to form sub-100 nm NPs in aqueous solution due to their very low critical micellar concentration (CMC). The resulting NPs show well controlled cisplatin loading yield, excellent acid-responsive drug release kinetics, and enhanced in vitro cytotoxicity against ovarian cancer cells as compared to free cisplatin. As an environmentally sensitive drug delivery vehicle, these NPs can potentially minimize the drug loss during NP circulation in the blood where the pH value is neutral and trigger rapid intracellular drug release after the NPs are endocytosed by the target cells. This characteristic drug release profile holds the promise to suppress cancer cell chemoresistance by rapidly releasing a high dose of chemotherapy drugs inside the tumor cells, thereby improving the therapeutic efficacy of the drug payload.

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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.

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Water-soluble, doxorubicin (DOX) conjugated gold nanoparticles (DOX conjugated Au NPs) exhibiting a significant pH-responsive drug release profile have been prepared and characterized in this study. The Au NPs were stabilized by thiolated methoxy polyethylene glycol (MPEG-SH) and methyl thioglycolate (MTG) at an equal molar ratio. The anticancer drug DOX was conjugated to the MTG segments of the thiol-stabilized Au NPs using hydrazine as the linker. The resulting hydrazone bonds formed between the DOX molecules and the MTG segments of the thiol-stabilized Au NPs are acid cleavable, thereby providing a strong pH-responsive drug release profile. The MPEG segments attached to the Au NPs provide the Au NPs with excellent solubility and stability in an aqueous medium while potentially enhancing the circulation time. The DOX loading level was determined to be 23 wt.%. The DOX release rate from the DOX conjugated Au NPs in an acid medium (i.e., pH 5.3) was dramatically higher than that in physiological conditions (i.e., pH 7.4). The DOX conjugated Au NPs and/or the DOX released from them were found both at the perinuclear regions and the nuclei of 4T1 tumor cells after incubation in a DOX conjugated Au NPs solution for 28 h. These novel DOX conjugated Au NPs have the potential to simultaneously enhance CT imaging contrast and facilitate photothermal cancer therapy while delivering anticancer drugs to their target sites.