Brian T. Luk

Nanoparticle biointerfacing by platelet membrane cloaking

Development of functional nanoparticles can be encumbered by unanticipated material properties and biological events, which can affect nanoparticle effectiveness in complex, physiologically relevant systems. Despite the advances in bottom-up nanoengineering and surface chemistry, reductionist functionalization approaches remain inadequate in replicating the complex interfaces present in nature and cannot avoid exposure of foreign materials. Here we report on the preparation of polymeric nanoparticles enclosed in the plasma membrane of human platelets, which are a unique population of cellular fragments that adhere to a variety of disease-relevant substrates. The resulting nanoparticles possess a right-side-out unilamellar membrane coating functionalized with immunomodulatory and adhesion antigens associated with platelets. Compared to uncoated particles, the platelet membrane-cloaked nanoparticles have reduced cellular uptake by macrophage-like cells and lack particle-induced complement activation in autologous human plasma. The cloaked nanoparticles also display platelet-mimicking properties such as selective adhesion to damaged human and rodent vasculatures as well as enhanced binding to platelet-adhering pathogens. In an experimental rat model of coronary restenosis and a mouse model of systemic bacterial infection, docetaxel and vancomycin, respectively, show enhanced therapeutic efficacy when delivered by the platelet-mimetic nanoparticles. The multifaceted biointerfacing enabled by the platelet membrane cloaking method provides a new approach in developing functional nanoparticles for disease-targeted delivery.

Cancer Cell Membrane-Coated Nanoparticles for Anticancer Vaccination and Drug Delivery

Cell-derived nanoparticles have been garnering increased attention due to their ability to mimic many of the natural properties displayed by their source cells. This top-down engineering approach can be applied toward the development of novel therapeutic strategies owing to the unique interactions enabled through the retention of complex antigenic information. Herein, we report on the biological functionalization of polymeric nanoparticles with a layer of membrane coating derived from cancer cells. The resulting core–shell nanostructures, which carry the full array of cancer cell membrane antigens, offer a robust platform with applicability toward multiple modes of anticancer therapy. We demonstrate that by coupling the particles with an immunological adjuvant, the resulting formulation can be used to promote a tumor-specific immune response for use in vaccine applications. Moreover, we show that by taking advantage of the inherent homotypic binding phenomenon frequently observed among tumor cells the membrane functionalization allows for a unique cancer targeting strategy that can be utilized for drug delivery applications.

A biomimetic nanosponge that absorbs pore-forming toxins

Detoxification treatments such as toxin-targeted anti-virulence therapy1, 2 offer ways to cleanse the body of virulence factors that are caused by bacterial infections, venomous injuries, and biological weaponry. Because existing detoxification platforms such as antisera3, monoclonal antibodies4, small-molecule inhibitors5, 6, and molecularly imprinted polymers7 act by targeting the molecular structures of the toxins, customized treatments are required for different diseases. Here we show a biomimetic toxin nanosponge that functions as a toxin decoy in vivo. The nanosponge, which consists of a polymeric nanoparticle core surrounded by red blood cell membranes, absorbs membrane-damaging toxins and diverts them away from their cellular targets. In a mouse model, the nanosponges markedly reduce the toxicity of staphylococcal alpha-hemolysin (α-toxin) and thus improve the survival rate of toxin-challenged mice. This biologically inspired toxin nanosponge presents a detoxification treatment that can potentially treat a variety of injuries and diseases caused by pore-forming toxins.

Nanoparticle-detained toxins for safe and effective vaccination

Toxoid vaccines—vaccines based on inactivated bacterial toxins— are routinely used to promote antitoxin immunity for the treatment and prevention of bacterial infections1–4. Following chemical or heat denaturation, inactivated toxins can be administered to mount toxin-specific immune responses. However, retaining faithful antigenic presentation while removing toxin virulence remains a major challenge and presents a trade-off between efficacy and safety in toxoid development. Here we show a nanoparticle-based toxin-detainment strategy that safely delivers non-disrupted pore-forming toxins for immune processing. Using erythrocyte membrane-coated nanoparticles and staphylococcal α-haemolysin, we demonstrate effective virulence neutralization via spontaneous particle entrapment. As compared to vaccination with heat-denatured toxin, mice vaccinated with the nanoparticle-detained toxin showed superior protective immunity against toxin adverse effects. We find that the non-disruptive detoxification approach benefited the immunogenicity and efficacy of toxoid vaccines. We anticipate the reported study to open new possibilities in the preparation of antitoxin vaccines against the many virulence factors that threaten public health.

Surface Functionalization of Gold Nanoparticles with Red Blood Cell Membranes

Gold nanoparticles are enclosed in cellular membranes derived from natural red blood cells (RBCs) by a top-down approach. The gold nanoparticles exhibit a complete membrane surface layer and biological characteristics of the source cells. The combination of inorganic gold nanoparticles with biological membranes is a compelling way to develop biomimetic gold nanostructures for future applications, such as those requiring evasion of the immune system.

Modulating Antibacterial Immunity via Bacterial Membrane-Coated Nanoparticles

Synthetic nanoparticles coated with cellular membranes have been increasingly explored to harness natural cell functions toward the development of novel therapeutic strategies. Herein, we report on a unique bacterial membrane-coated nanoparticle system as a new and exciting antibacterial vaccine. Using Escherichia coli as a model pathogen, we collect bacterial outer membrane vesicles (OMVs) and successfully coat them onto small gold nanoparticles (AuNPs) with a diameter of 30 nm. The resulting bacterial membrane-coated AuNPs (BM-AuNPs) show markedly enhanced stability in biological buffer solutions. When injected subcutaneously, the BM-AuNPs induce rapid activation and maturation of dendritic cells in the lymph nodes of the vaccinated mice. In addition, vaccination with BM-AuNPs generates antibody responses that are durable and of higher avidity than those elicited by OMVs only. The BM-AuNPs also induce an elevated production of interferon gamma (INFγ) and interleukin-17 (IL-17), but not interleukin-4 (IL-4), indicating its capability of generating strong Th1 and Th17 biased cell responses against the source bacteria. These observed results demonstrate that using natural bacterial membranes to coat synthetic nanoparticles holds great promise for designing effective antibacterial vaccines.

Lipid- and Polymer-Based Nanostructures for Cancer Theranostics

The relatively new field of nanotheranostics combines the advantages of in vivo diagnosis with the ability to administer treatment through a single nano-sized carrier, offering new opportunities for cancer diagnosis and therapy. Nanotheranostics has facilitated the development of nanomedicine through direct visualization of drug blood circulation and biodistribution. From a clinical perspective, nanotheranostics allows therapies to be administered and monitored in real time, thus decreasing the potential of under- or over-dosing and allowing for more personalized treatment regimens. Herein, we review recent development of nanotheranostics using lipid- and polymer-based formulations, with a particular focus on their applications in cancer research. Recent advances in nanotechnology aimed to combine therapeutic molecules with imaging agents for magnetic resonance imaging, radionuclide imaging, or fluorescence imaging are discussed.

Current Advances in Polymer-Based Nanotheranostics for Cancer Treatment and Diagnosis

Nanotheranostics is a relatively new, fast-growing field that combines the advantages of treatment and diagnosis via a single nanoscale carrier. The ability to bundle both therapeutic and diagnostic capabilities into one package offers exciting prospects for the development of novel nanomedicine. Nanotheranostics can deliver treatment while simultaneously monitoring therapy response in real-time, thereby decreasing the potential of over- or under-dosing patients. Polymer-based nanomaterials, in particular, have been used extensively as carriers for both therapeutic and bioimaging agents and thus hold great promise for the construction of multifunctional theranostic formulations. Herein, we review recent advances in polymer-based systems for nanotheranostics, with a particular focus on their applications in cancer research. We summarize the use of polymer nanomaterials for drug delivery, gene delivery, and photodynamic therapy, combined with imaging agents for magnetic resonance imaging, radionuclide imaging, and fluorescence imaging.

Lipid-insertion enables targeting functionalization of erythrocyte membrane-cloaked nanoparticles

RBC membrane-cloaked polymeric nanoparticles represent an emerging nanocarrier platform with extended circulation in vivo. A lipid-insertion method is employed to functionalize these nanoparticles without the need for direct chemical conjugation. Insertion of both folate and the nucleolin-targeting aptamer AS1411 shows receptor-specific targeting against model cancer cell lines.

Clearance of pathological antibodies using biomimetic nanoparticles

Significance The selective depletion of disease-causing antibodies using nanoparticles offers a new model in the management of type II immune hypersensitivity reactions. The demonstration of pathophysiologically inspired nanoengineering serves as a valuable prototype for additional therapeutic improvements with the goal of minimizing therapy-related adverse effects. Through the use of cell membrane-cloaked nanoparticles, nanoscale decoys with strong affinity to pathological antibodies can be administered to disrupt disease processes in a minimally toxic manner. These biomimetic nanoparticles enable indiscriminate absorption of pathological antibodies regardless of their epitope specificities. This particular approach offers much promise in treating antibody-mediated autoimmune diseases, in which target antigens on susceptible cells can vary from patient to patient. Pathological antibodies have been demonstrated to play a key role in type II immune hypersensitivity reactions, resulting in the destruction of healthy tissues and leading to considerable morbidity for the patient. Unfortunately, current treatments present significant iatrogenic risk while still falling short for many patients in achieving clinical remission. In the present work, we explored the capability of target cell membrane-coated nanoparticles to abrogate the effect of pathological antibodies in an effort to minimize disease burden, without the need for drug-based immune suppression. Inspired by antibody-driven pathology, we used intact RBC membranes stabilized by biodegradable polymeric nanoparticle cores to serve as an alternative target for pathological antibodies in an antibody-induced anemia disease model. Through both in vitro and in vivo studies, we demonstrated efficacy of RBC membrane-cloaked nanoparticles to bind and neutralize anti-RBC polyclonal IgG effectively, and thus preserve circulating RBCs.