The advent of nanomedicine has had a tremendous impact on patient outcomes in the clinic. At the nanoscale, drug- loaded particles exhibit unique attributes that allow them to be more efficacious compared to free drug formulations, leading to better standard of care as well as increased patient compliance. Since the approval of Doxil, a liposomal formulation of the chemotherapy drug doxorubicin, two decades ago, researchers have been focused on leveraging nanotechnology to solve many of the hurdles in modern medicine. Despite the tremendous progress that has been made on this front, there is still much room for improvement. One major challenge in nanomedicine exists at the interface between synthetic nanomaterials and natural biological systems. My work has focused on a novel strategy for addressing the challenge of effective biointerfacing. This involves using natural membrane derived from the surface of cells to camouflage synthetic nanomaterials for the design of more effective and novel therapeutic modalities. The first portion of this thesis will focus on the design of long-circulating drug delivery carriers by using a red blood cell membrane cloaking strategy to prolong systemic half-life. Building upon an initially reported red blood cell membrane-coated nanoparticle platform, drug-loaded nanocarriers are designed that can be actively targeted to tumors. Not only does natural membrane cloaking enable prolonged circulation for more effective drug delivery, but the presence of the natural membrane coating also facilitates the development of entirely new therapeutic modalities. The second part of this thesis will focus on the use of membrane-coated nanoparticles for the clearance of pathologic moieties. This is demonstrated for both pore- forming toxins that are secreted by bacteria and autoimmune antibodies targeting red blood cells. The final part of this thesis will outline the use of membrane- coated particles for specifically modulating the immune system. The concept is demonstrated for vaccination against both pathogen-derived toxins as well as against autologous cancer cells. Ultimately, the cell membrane- coated nanoparticle platform has the potential to greatly change the landscape of nanomedicine. From more effective drug delivery carriers to novel applications that have yet to be discovered, there are many avenues still waiting to be fully explored

Vaccination is a modality that has been widely explored for the treatment of various diseases. To increase the potency of vaccine formulations, immunostimulatory adjuvants have been regularly exploited, and the stimulator of interferon genes (STING) signaling pathway has recently emerged as a remarkable therapeutic target. STING is an endogenous protein on the endoplasmic reticulum that is a downstream sensor to cytosolic DNA. Upon activation, STING initiates a series of intracellular signaling cascades that ultimately generate potent type I interferon-mediated immune responses. Both natural and synthetic agonists have been used to stimulate the STING pathway, but they are usually administered locally due to low bioavailability, instability, and difficulty in bypassing the plasma membrane. With excellent pharmacokinetic profiles and versatility, nanocarriers can address many of these challenges and broaden the application of STING vaccines. Along these lines, STING-inducing nanovaccines are being developed to address a wide range of diseases. In this review, we discuss the recent advances in STING nanovaccines for anticancer, antiviral, and antibacterial applications.

Phototherapy is an emerging approach for cancer treatment that is effective at controlling the growth of primary tumors. In the presence of light irradiation, photothermal and photodynamic agents that are delivered to tumor sites can induce local hyperthermia and the production of reactive oxygen species, respectively, that directly eradicate cancer cells. Nanoparticles, characterized by their small size and tunable physiochemical properties, have been widely utilized as carriers for phototherapeutic agents to improve their biocompatibility and tumor-targeted delivery. Nanocarriers can also be used to implement various codelivery strategies for further enhancing phototherapeutic efficiency. More recently, there has been considerable interest in augmenting the immunological effects of nanoparticle-based phototherapies, which can yield durable and systemic antitumor responses. This review provides an overview of recent developments in using nanoparticle technology to achieve photo-immunotherapy.

Nanoparticulate platforms have contributed significantly to the field of biomedical research, demonstrating advantages over traditional modalities in areas such as drug delivery, detoxification, and vaccination. When it comes to the design of nanoparticles, biomimetic strategies have become increasingly popular as a means of promoting effective interactions with biological systems. A recently developed cell membrane-coated nanoparticle platform can leverage the natural interactions that cells engage in with other cells, the extracellular matrix, and biomolecules in order to reduce undesirable nonspecific interactions, while increasing target-specific interactions. Here, we discuss the current state of these biomimetic nanoparticles and highlight how they can be used for various biomedical applications.

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.

Cardiovascular disease (CVD), which encompasses a number of conditions that can affect the heart and blood vessels, presents a major challenge for modern-day healthcare. Nearly one in three people has some form of CVD, with many suffering from multiple or intertwined conditions that can ultimately lead to traumatic events such as a heart attack or stroke. While the knowledge obtained in the past century regarding the cardiovascular system has paved the way for the development of life-prolonging drugs and treatment modalities, CVD remains one of the leading causes of death in developed countries. More recently, researchers have explored the application of nanotechnology to improve upon current clinical paradigms for the management of CVD. Nanoscale delivery systems have many advantages, including the ability to target diseased sites, improve drug bioavailability, and carry various functional payloads. In this review, we cover the different ways in which nanoparticle technology can be applied towards CVD diagnostics and treatments. The development of novel biomimetic platforms with enhanced functionalities is discussed in detail.

Acinetobacter baumannii is a leading cause of antibiotic-resistant nosocomial infections with high mortality rates, yet there is currently no clinically approved vaccine formulation. During the onset of A. baumannii infection, neutrophils are the primary responders and play a major role in resisting the pathogen. Here, we design a biomimetic nanotoxoid for antivirulence vaccination by using neutrophil membrane-coated nanoparticles to safely capture secreted A. baumannii factors. Vaccination with the nanotoxoid formulation rapidly mobilizes innate immune cells and promotes pathogen-specific adaptive immunity. In murine models of pneumonia, septicemia, and superficial wound infection, immunization with the nanovaccine offers significant protection, improving survival and reducing signs of acute inflammation. Lower bacterial burdens are observed in vaccinated animals regardless of the infection route. Altogether, neutrophil nanotoxoids represent an effective platform for eliciting multivalent immunity to protect against multidrug-resistant A. baumannii in a wide range of disease conditions.

While traditional approaches for disease management in the era of modern medicine have saved countless lives and enhanced patient well-being, it is clear that there is significant room to improve upon the current status quo. For infectious diseases, the steady rise of antibiotic resistance has resulted in super pathogens that do not respond to most approved drugs. In the field of cancer treatment, the idea of a cure-all silver bullet has long been abandoned. As a result of the challenges facing current treatment and prevention paradigms in the clinic, there is an increasing push for personalized therapeutics, where plans for medical care are established on a patient-by-patient basis. Along these lines, vaccines, both against bacteria and tumors, are a clinical modality that could benefit significantly from personalization. Effective vaccination strategies could help to address many challenging disease conditions, but current vaccines are limited by factors such as a lack of potency and antigenic breadth. Recently, researchers have turned toward the use of biomimetic nanotechnology as a means of addressing these hurdles. Recent progress in the development of biomimetic nanovaccines for antibacterial and anticancer applications is discussed, with an emphasis on their potential for personalized medicine.

Immunostimulatory agents, including adjuvants, cytokines, and monoclonal antibodies, hold great potential for the treatment of cancer. However, their direct administration often results in suboptimal pharmacokinetics, vulnerability to biodegradation, and compromised targeting. More recently, encapsulation into biocompatible nanoparticulate carriers has become an emerging strategy for improving the delivery of these immunotherapeutic agents. Such approaches can address many of the challenges facing current treatment modalities by endowing additional protection and significantly elevating the bioavailability of the encapsulated payloads. To further improve the delivery efficiency and subsequent immune responses associated with current nanoscale approaches, biomimetic modifications and materials have been employed to create delivery platforms with enhanced functionalities. By leveraging nature-inspired design principles, these biomimetic nanodelivery vehicles have the potential to alter the current clinical landscape of cancer immunotherapy.

The rational design and application of mRNA-based medicine have recently yielded some key successes in the clinical management of human diseases. mRNA technology allows for the facile and direct production of proteins in vivo, thus circumventing the need for lengthy drug development cycles and complex production workflows. As such, mRNA formulations can significantly improve upon the biological therapies that have become commonplace in modern medicine. Despite its many advantages, mRNA is inherently fragile and has specific delivery requirements. Leveraging the engineering flexibility of nanobiotechnology, mRNA payloads can be incorporated into nanoformulations such that they do not invoke unwanted immune responses, are targeted to tissues of interest, and can be delivered to the cytosol, resulting in improved safety while enhancing bioactivity. With the rapidly evolving landscape of nanomedicine, novel technologies that are under development have the potential to further improve the clinical utility of mRNA medicine. This review covers the design principles relevant to engineering mRNA-based nanomedicine platforms. It also details the current research on mRNA nanoformulations for addressing viral infections, cancers, and genetic diseases. Given the trends in the field, future mRNA-based nanomedicines have the potential to change how many types of diseases are managed in the clinic.