New advances in biomaterial-based approaches to modulate the immune system are being applied to treat cancer, infectious diseases, and autoimmunity. Particulate systems are especially well-suited to deliver immunomodulatory factors to immune cells since their small size allows them to engage cell surface receptors or deliver cargo intracellularly after internalization. Biodegradable polymeric particles are a particularly versatile platform for the delivery of signals to the immune system because they can be easily surface-modified to target specific receptors and engineered to release encapsulated cargo in a precise, sustained manner. Micro- and nanoscale systems have been used to deliver a variety of therapeutic agents including monoclonal antibodies, peptides, and small molecule drugs that function to activate the immune system against cancer or infectious disease, or suppress the immune system to combat autoimmune diseases and transplant rejection. This review provides an overview of recent advances in the development of polymeric micro- and nanoparticulate systems for the presentation and delivery of immunomodulatory agents targeted to a variety of immune cell types including APCs, T cells, B cells, and NK cells.
Anisotropic polymeric particles are of growing interest for biomaterials applications due to their unique properties. These include the ability for these particles to evade nonspecific cellular uptake and to have enhanced targeted cellular uptake and interaction. One of the most widely used methods for generating anisotropic polymeric particles is the thin film stretching procedure. Despite its theoretical simplicity, this procedure, as it has been implemented to date, can be difficult due to the inconsistent nature of the manual operation of machinery used to stretch the film. We have constructed an automated thin film stretcher for control over biomaterials via thin film stretching in 1D and 2D and as a result, have enabled precise generation of anisotropic polymeric particles. We demonstrate that this device can be utilized to produce anisotropic biodegradable particles of different size, shape, and material consistency. Furthermore, we show that this machine has enabled the scaled up and rapid production of anisotropic polymeric particles, including polymeric microparticles that mimic the shape of red blood cells. Further application of this automated thin film stretching device could allow for significant impact to diverse biomaterial and biomedical applications such as biomimetic particles for immunoengineering and long-circulating particles for controlled release of drugs.
mRNA gene therapy has recently emerged as a candidate to enable multiple therapeutic applications including protein replacement therapy, vaccine immunology, and regenerative medicine. Despite the extensive therapeutic potential, the successful clinical translation of mRNA gene therapies has been very limited in practice due to the inadequate understanding of how to target various organs or cell type for protein expression. Multiple studies in the past decade have demonstrated carrier material properties and routes of administration as significant parameters influencing the expression profile of mRNA therapeutics. However, the disparate nature of these reports has prevented critical and global understanding of how these factors contribute to organ targeting for mRNA delivery. Elucidation of trends and commonalities in materials achieving tissue specific mRNA delivery may enable the realization of the medical and commercial promise of therapeutic mRNA medicines. The purpose of this review is to provide a thorough and robust meta-analysis of the various materials that have been successfully used to target different organs for mRNA delivery. The article summarizes the distinct properties of the materials used as well as evaluates various routes of administration of mRNA therapeutics and the applications that can be achieved. This review will therefore serve as useful guide for the community in the development of future materials for mRNA delivery to enable the full potential of this nucleic acid modality for gene therapy.
Nonspherical ellipsoidal nanodimensional artificial antigen-presenting cells (aAPCs) are fabricated by J. J. Green and co-workers and on page 1519 they are shown to have superior T-Cell activation and pharmacokinetic properties compared to equivalent spherical nanodimensional aAPCs. Shown on the cover are transmission electron microscopy images of the ellipsoidal nanoparticles interacting with a computer generated T-Cell membrane as nano aAPCs. Due to their larger radius of curvature, ellipsoidal nano aAPCs are more effective at biomimicry of natural APCs for antigen-specific T-Cell activation.
Triggering shape-memory functionality under clinical hyperthermia temperatures could enable the control and actuation of shape-memory systems in clinical practice. For this purpose, we developed light-inducible shape-memory microparticles composed of a poly(d,l-lactic acid) (PDLLA) matrix encapsulating gold nanoparticles (Au@PDLLA hybrid microparticles). This shape-memory polymeric system for the first time demonstrates the capability of maintaining an anisotropic shape at body temperature with triggered shape-memory effect back to a spherical shape at a narrow temperature range above body temperature with a proper shape recovery speed (37 < T < 45 °C). We applied a modified film-stretching processing method with carefully controlled stretching temperature to enable shape memory and anisotropy in these micron-sized particles. Accordingly, we achieved purely entanglement-based shape-memory response without chemical cross-links in the miniaturized shape-memory system. Furthermore, these shape-memory microparticles exhibited light-induced spatiotemporal control of their shape recovery using a laser to trigger the photothermal heating of doped gold nanoparticles. This shape-memory system is composed of biocompatible components and exhibits spatiotemporal controllability of its properties, demonstrating a potential for various biomedical applications, such as tuning macrophage phagocytosis as demonstrated in this study.
Non-spherical nanodimensional artificial antigen presenting cells (naAPCs) offer the potential to systemically induce an effective antigen-specific immune response. In this report it is shown biodegradable ellipsoidal naAPCs mimic the T-Cell/APC interaction better than equivalent spherical naAPCs. In addition, it is demonstrated ellipsoidal naAPCs offer reduced non-specific cellular uptake and a superior pharmacokinetic profile compared to spherical naAPCs.
