Ex vivo expansion and hydrogel-mediated in vivo delivery of tissue-resident memory T cells for immunotherapy.

Tissue-resident memory T (T) cells preferentially reside in peripheral tissues, serving as key players in tumor immunity and immunotherapy. The lack of effective approaches for expanding T cells and delivering these cells in vivo hinders the exploration of T cell-mediated cancer immunotherapy. Here, we report a nanoparticle artificial antigen-presenting cell (nano-aAPC) ex vivo expansion approach and an in vivo delivery system for T cells.

Alginate-based artificial antigen presenting cells expand functional CD8 T cells with memory characteristics for adoptive cell therapy.

The development of artificial Antigen Presenting Cells (aAPCs) has led to improvements in adoptive T cell therapy (ACT), an immunotherapy, for cancer treatment. aAPCs help to streamline the consistent production and expansion of T cells, thus reducing the time and costs associated with ACT. However, several issues still exist with ACT, such as insufficient T cell potency, which diminishes the translational potential for ACT.

Supramolecular assembly of polycation/mRNA nanoparticles and in vivo monocyte programming.

Size-dependent phagocytosis is a well-characterized phenomenon in monocytes and macrophages. However, this size effect for preferential gene delivery to these important cell targets has not been fully exploited because commonly adopted stabilization methods for electrostatically complexed nucleic acid nanoparticles, such as PEGylation and charge repulsion, typically arrest the vehicle size below 200 nm. Here, we bridge the technical gap in scalable synthesis of larger submicron gene delivery vehicles by electrostatic self-assembly of charged nanoparticles, facilitated by a polymer structurally designed to modulate internanoparticle Coulombic and van der Waals forces.

Suprachoroidal gene transfer with nonviral nanoparticles in large animal eyes.

Suprachoroidal nonviral gene therapy with biodegradable poly(β-amino ester) nanoparticles (NPs) provides widespread expression in photoreceptors and retinal pigmented epithelial (RPE) cells and therapeutic benefits in rodents. Here, we show in a human-sized minipig eye that suprachoroidal injection of 50 μl of NPs containing 19.2 μg of GFP expression plasmid caused GFP expression in photoreceptors and RPE throughout the entire eye with no toxicity.

Polymeric nanoparticle gel for intracellular mRNA delivery and immunological reprogramming of tumors.

Immuno-oncology therapies have been of great interest with the goal of inducing sustained tumor regression, but clinical results have demonstrated the need for improved and widely applicable methods. An antigen-free method of cancer immunotherapy can stimulate the immune system to recruit lymphocytes and produce immunostimulatory factors without prior knowledge of neoantigens, while local delivery reduces the risk of systemic toxicity. To improve the interactions between tumor cells and cytotoxic lymphocytes, a gene delivery nanoparticle platform was engineered to reprogram the tumor microenvironment (TME) in situ to be more immunostimulatory by inducing tumor-associated antigen-presenting cells (tAPCs) to activate cytotoxic lymphocytes against the tumor.

Shape matters: Biodegradable anisotropic nanoparticle artificial antigen presenting cells for cancer immunotherapy.

Artificial antigen presenting cells are biomimetic particles that recapitulate the signals presented by natural antigen presenting cells in order to stimulate T cells in an antigen-specific manner using an acellular platform. We have engineered an enhanced nanoscale biodegradable artificial antigen presenting cell by modulating particle shape to achieve a nanoparticle geometry that allows for increased radius of curvature and surface area for T cell contact. The non-spherical nanoparticle artificial antigen presenting cells developed here have reduced nonspecific uptake and improved circulation time compared both to spherical nanoparticles and to traditional microparticle technologies.

Nanoparticle-based modulation of CD4 T cell effector and helper functions enhances adoptive immunotherapy.

Helper (CD4) T cells perform direct therapeutic functions and augment responses of cells such as cytotoxic (CD8) T cells against a wide variety of diseases and pathogens. Nevertheless, inefficient synthetic technologies for expansion of antigen-specific CD4 T cells hinders consistency and scalability of CD4 T cell-based therapies, and complicates mechanistic studies. Here we describe a nanoparticle platform for ex vivo CD4 T cell culture that mimics antigen presenting cells (APC) through display of major histocompatibility class II (MHC II) molecules.

Approaches towards biomaterial-mediated gene editing for cancer immunotherapy.

Gene therapies are transforming treatment modalities for many human diseases and disorders, including those in ophthalmology, oncology, and nephrology. To maximize the clinical efficacy and safety of these treatments, consideration of both delivery materials and cargos is critical. In consideration of the former, a large effort has been placed on transitioning away from potentially immunoreactive and toxic viral delivery mechanisms towards safer and highly tunable nonviral delivery mechanisms, including polymeric, lipid-based, and inorganic carriers.