Biomimetic nanoparticles for anti-inflammatory therapy

Nanomedicine is a flourishing scientific field involving the design and control of matter on the nanometer scale for therapeutic use. One emerging avenue within the nanomedicine field is biodetoxification-based therapy, in which nano-sized structures are used to capture and retain biotoxins that would otherwise attack host cells, cause cellular damage, and trigger damage-associated signaling pathways to propagate diseases. Particularly, inflammation is a biological process that involves complex signaling networks and disease-specific cellular responses, posing significant challenge for designing medicine with high specificity and potency. To this end, the design flexibility of nanoparticle size and surface modification, and unique particle-cell interaction at the nanoscale can lead to novel and efficacious routes for anti-inflammatory therapy. Herein, we discuss the new generations of cell membrane-coated nanoparticles specifically tailored for biodetoxification-based anti-inflammatory therapy. Firstly, recent advances in neutralizing inflammatory cytokine will be discussed. The second portion of this dissertation will present neutrophil membrane-coated nanoparticle (neutrophil-NP) for therapeutic treatment of inflammatory arthritis. Neutrophil-NPs targeted and penetrated into the inflamed tissue, and effectively neutralized inflammatory cytokines. The third portion will cover the development of macrophage membrane-coated nanoparticle for neutralization of bacterial endotoxin and inflammatory cytokines, and management of bacterial sepsis. Finally, we will focus on the design of a unique ‘lure and kill’ nanoparticle for effective inhibition of phospholipase A2 (PLA2). The cell membrane works synergistically with a PLA2 attractant to ‘lure’ PLA2 for attack, then the PLA2 inhibitor in the cell membrane further ‘kills’ the enzyme. With effective inhibition of venomous PLA2, these nanoparticles further demonstrated strong inhibitory activity against PLA2 and attenuation of the inflammatory cascade during acute pancreatitis progression. This dissertation will serve as a paradigm for rational design of cell membrane-coated nanoparticles for therapeutic treatment of inflammatory disorders. By tapping into the biological challenges associated with anti-inflammatory therapy, cell membrane-coated nanoparticles can be tailored towards its designated biological target. By harnessing the design flexibility, this nanotechnology holds great potential to be developed into a class of drug-free anti-inflammatory nanomedicine that will be extraordinarily valuable for biomedical researchers and clinicians alike

Biomimetic nanoparticles for anti-inflammatory therapy

Nanomedicine is a flourishing scientific field involving the design and control of matter on the nanometer scale for therapeutic use. One emerging avenue within the nanomedicine field is biodetoxification-based therapy, in which nano-sized structures are used to capture and retain biotoxins that would otherwise attack host cells, cause cellular damage, and trigger damage-associated signaling pathways to propagate diseases. Particularly, inflammation is a biological process that involves complex signaling networks and disease-specific cellular responses, posing significant challenge for designing medicine with high specificity and potency. To this end, the design flexibility of nanoparticle size and surface modification, and unique particle-cell interaction at the nanoscale can lead to novel and efficacious routes for anti-inflammatory therapy. Herein, we discuss the new generations of cell membrane-coated nanoparticles specifically tailored for biodetoxification-based anti-inflammatory therapy. Firstly, recent advances in neutralizing inflammatory cytokine will be discussed. The second portion of this dissertation will present neutrophil membrane-coated nanoparticle (neutrophil-NP) for therapeutic treatment of inflammatory arthritis. Neutrophil-NPs targeted and penetrated into the inflamed tissue, and effectively neutralized inflammatory cytokines. The third portion will cover the development of macrophage membrane-coated nanoparticle for neutralization of bacterial endotoxin and inflammatory cytokines, and management of bacterial sepsis. Finally, we will focus on the design of a unique ‘lure and kill’ nanoparticle for effective inhibition of phospholipase A2 (PLA2). The cell membrane works synergistically with a PLA2 attractant to ‘lure’ PLA2 for attack, then the PLA2 inhibitor in the cell membrane further ‘kills’ the enzyme. With effective inhibition of venomous PLA2, these nanoparticles further demonstrated strong inhibitory activity against PLA2 and attenuation of the inflammatory cascade during acute pancreatitis progression. This dissertation will serve as a paradigm for rational design of cell membrane-coated nanoparticles for therapeutic treatment of inflammatory disorders. By tapping into the biological challenges associated with anti-inflammatory therapy, cell membrane-coated nanoparticles can be tailored towards its designated biological target. By harnessing the design flexibility, this nanotechnology holds great potential to be developed into a class of drug-free anti-inflammatory nanomedicine that will be extraordinarily valuable for biomedical researchers and clinicians alike

Nanoparticle approaches against SARS-CoV-2 infection.

Coronavirus disease 2019 (COVID-19), caused by the highly contagious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become the worst pandemic disease of the current millennium. To address this crisis, therapeutic nanoparticles, including inorganic nanoparticles, lipid nanoparticles, polymeric nanoparticles, virus-like nanoparticles, and cell membrane-coated nanoparticles, have all offered compelling antiviral strategies. This article reviews these strategies in three categories: (1) nanoparticle-enabled detection of SARS-CoV-2, (2) nanoparticle-based treatment for COVID-19, and (3) nanoparticle vaccines against SARS-CoV-2. We discuss how nanoparticles are tailor-made to biointerface with the host and the virus in each category. For each nanoparticle design, we highlight its structure-function relationship that enables effective antiviral activity. Overall, nanoparticles bring numerous new opportunities to improve our response to the current COVID-19 pandemic and enhance our preparedness for future viral outbreaks

Lure-and-kill macrophage nanoparticles alleviate the severity of experimental acute pancreatitis.

Acute pancreatitis is a disease associated with suffering and high lethality. Although the disease mechanism is unclear, phospholipase A2 (PLA2) produced by pancreatic acinar cells is a known pathogenic trigger. Here, we show macrophage membrane-coated nanoparticles with a built-in 'lure and kill' mechanism (denoted 'MΦ-NP(L&K)') for the treatment of acute pancreatitis. MΦ-NP(L&K) are made with polymeric cores wrapped with natural macrophage membrane doped with melittin and MJ-33. The membrane incorporated melittin and MJ-33 function as a PLA2 attractant and a PLA2 inhibitor, respectively. These molecules, together with membrane lipids, work synergistically to lure and kill PLA2 enzymes. These nanoparticles can neutralize PLA2 activity in the sera of mice and human patients with acute pancreatitis in a dose-dependent manner and suppress PLA2-induced inflammatory response accordingly. In mouse models of both mild and severe acute pancreatitis, MΦ-NP(L&K) confer effective protection against disease-associated inflammation, tissue damage and lethality. Overall, this biomimetic nanotherapeutic strategy offers an anti-PLA2 treatment option that might be applicable to a wide range of PLA2-mediated inflammatory disorders

Multimodal Enzyme Delivery and Therapy Enabled by Cell Membrane-Coated Metal–Organic Framework Nanoparticles

Therapeutic enzymes used for genetic disorders or metabolic diseases oftentimes suffer from suboptimal pharmacokinetics and stability. Nanodelivery systems have shown considerable promise for improving the performance of enzyme therapies. Here, we develop a cell membrane-camouflaged metal-organic framework (MOF) system with enhanced biocompatibility and functionality. The MOF core can efficiently encapsulate enzymes while maintaining their bioactivity. After the introduction of natural cell membrane coatings, the resulting nanoformulations can be safely administered in vivo. The surface receptors on the membrane can also provide additional functionalities that synergize with the encapsulated enzyme to target disease pathology from multiple dimensions. Employing uricase as a model enzyme, we demonstrate the utility of this approach in multiple animal disease models. The results support the use of cell membrane-coated MOFs for enzyme delivery, and this strategy could be leveraged to improve the usefulness of enzyme-based therapies for managing a wide range of important human health conditions

Emerging Approaches to Functionalizing Cell Membrane-Coated Nanoparticles

There has been significant interest in developing cell membrane-coated nanoparticles due to their unique abilities of biomimicry and biointerfacing. As the technology progresses, it becomes clear that the application of these nanoparticles can be drastically broadened if additional functions beyond those derived from the natural cell membranes can be integrated. Herein, we summarize the most recent advances in the functionalization of cell membrane-coated nanoparticles. In particular, we focus on emerging methods, including (1) lipid insertion, (2) membrane hybridization, (3) metabolic engineering, and (4) genetic modification. These approaches contribute diverse functions in a nondisruptive fashion while preserving the natural function of the cell membranes. They also improve on the multifunctional and multitasking ability of cell membrane-coated nanoparticles, making them more adaptive to the complexity of biological systems. We hope that these approaches will serve as inspiration for more strategies and innovations to advance cell membrane coating technology

Lure-and-kill macrophage nanoparticles alleviate the severity of experimental acute pancreatitis.

Acute pancreatitis is a disease associated with suffering and high lethality. Although the disease mechanism is unclear, phospholipase A2 (PLA2) produced by pancreatic acinar cells is a known pathogenic trigger. Here, we show macrophage membrane-coated nanoparticles with a built-in 'lure and kill' mechanism (denoted 'MΦ-NP(L&K)') for the treatment of acute pancreatitis. MΦ-NP(L&K) are made with polymeric cores wrapped with natural macrophage membrane doped with melittin and MJ-33. The membrane incorporated melittin and MJ-33 function as a PLA2 attractant and a PLA2 inhibitor, respectively. These molecules, together with membrane lipids, work synergistically to lure and kill PLA2 enzymes. These nanoparticles can neutralize PLA2 activity in the sera of mice and human patients with acute pancreatitis in a dose-dependent manner and suppress PLA2-induced inflammatory response accordingly. In mouse models of both mild and severe acute pancreatitis, MΦ-NP(L&K) confer effective protection against disease-associated inflammation, tissue damage and lethality. Overall, this biomimetic nanotherapeutic strategy offers an anti-PLA2 treatment option that might be applicable to a wide range of PLA2-mediated inflammatory disorders

Drug Targeting via Platelet Membrane–Coated Nanoparticles

Platelets possess distinct surface moieties responsible for modulating their adhesion to various disease-relevant substrates involving vascular damage, immune evasion, and pathogen interactions. Such broad biointerfacing capabilities of platelets have inspired the development of platelet-mimicking drug carriers that preferentially target drug payloads to disease sites for enhanced therapeutic efficacy. Among these carriers, platelet membrane-coated nanoparticles (denoted 'PNPs') made by cloaking synthetic substrates with the plasma membrane of platelets have emerged recently. Their 'top-down' design combines the functionalities of natural platelet membrane and the engineering flexibility of synthetic nanomaterials, which together create synergy for effective drug delivery and novel therapeutics. Herein, we review the recent progress of engineering PNPs with different structures for targeted drug delivery, focusing on three areas, including targeting injured blood vessels to treat vascular diseases, targeting cancer cells for cancer treatment and detection, and targeting drug-resistant bacteria to treat infectious diseases. Overall, current studies have established PNPs as versatile nanotherapeutics for drug targeting with strong potentials to improve the treatment of various diseases

CD4+ T Cell-Mimicking Nanoparticles Broadly Neutralize HIV-1 and Suppress Viral Replication through Autophagy.

Therapeutic strategies that provide effective and broad-spectrum neutralization against HIV-1 infection are highly desirable. Here, we investigate the potential of nanoengineered CD4+ T cell membrane-coated nanoparticles (TNP) to neutralize a broad range of HIV-1 strains. TNP displayed outstanding neutralizing breadth and potency; they neutralized all 125 HIV-1-pseudotyped viruses tested, including global subtypes/recombinant forms, and transmitted/founder viruses, with a geometric mean 80% inhibitory concentration (IC80) of 819 μg ml-1 (range, 72 to 8,570 μg ml-1). TNP also selectively bound to and induced autophagy in HIV-1-infected CD4+ T cells and macrophages, while having no effect on uninfected cells. This TNP-mediated autophagy inhibited viral release and reduced cell-associated HIV-1 in a dose- and phospholipase D1-dependent manner. Genetic or pharmacological inhibition of autophagy ablated this effect. Thus, we can use TNP as therapeutic agents to neutralize cell-free HIV-1 and to target HIV-1 gp120-expressing cells to decrease the HIV-1 reservoir.IMPORTANCE HIV-1 is a major global health challenge. The development of an effective vaccine and/or a therapeutic cure is a top priority. The creation of vaccines that focus an antibody response toward a particular epitope of a protein has shown promise, but the genetic diversity of HIV-1 hinders this progress. Here we developed an approach using nanoengineered CD4+ T cell membrane-coated nanoparticles (TNP). Not only do TNP effectively neutralize all strains of HIV-1, but they also selectively bind to infected cells and decrease the release of HIV-1 particles through an autophagy-dependent mechanism with no drug-induced off-target or cytotoxic effects on bystander cells