Combination delivery of TGF-β inhibitor and IL-2 by nanoscale liposomal polymeric gels enhances tumour immunotherapy.

The tumour microenvironment thwarts conventional immunotherapy through multiple immunologic mechanisms, such as the secretion of the transforming growth factor-β (TGF-β), which stunts local tumour immune responses. Therefore, high doses of interleukin-2 (IL-2), a conventional cytokine for metastatic melanoma, induces only limited responses. To overcome the immunoinhibitory nature of the tumour microenvironment, we developed nanoscale liposomal polymeric gels (nanolipogels; nLGs) of drug-complexed cyclodextrins and cytokine-encapsulating biodegradable polymers that can deliver small hydrophobic molecular inhibitors and water-soluble protein cytokines in a sustained fashion to the tumour microenvironment.

Role of sustained antigen release from nanoparticle vaccines in shaping the T cell memory phenotype.

Particulate vaccines are emerging promising technologies for the creation of tunable prophylactics against a wide variety of conditions. Vesicular and solid biodegradable polymer platforms, exemplified by liposomes and polyesters, respectively, are two of the most ubiquitous platforms in vaccine delivery studies. Here we directly compared the efficacy of each in a long-term immunization study and in protection against a model bacterial antigen.

Pathogen-associated molecular patterns on biomaterials: a paradigm for engineering new vaccines.

Vaccine development has progressed significantly and has moved from whole microorganisms to subunit vaccines that contain only their antigenic proteins. Subunit vaccines are often less immunogenic than whole pathogens; therefore, adjuvants must amplify the immune response, ideally establishing both innate and adaptive immunity. Incorporation of antigens into biomaterials, such as liposomes and polymers, can achieve a desired vaccine response.

The impact of nanoparticle ligand density on dendritic-cell targeted vaccines.

Dendritic-cell (DC) targeted antigen delivery systems hold promise for enhancing vaccine efficacy and delivery of therapeutics. However, it is not known how the number and density of targeting ligands on such systems may affect DC function and subsequent T cell response. We modified the surface of biodegradable nanoparticles loaded with antigen with different densities of the mAb to the DC lectin DEC-205 receptor and assessed changes in the cytokine response of DCs and T cells.

TLR9-targeted biodegradable nanoparticles as immunization vectors protect against West Nile encephalitis.

Vaccines that activate humoral and cell-mediated immune responses are urgently needed for many infectious agents, including the flaviviruses dengue and West Nile (WN) virus. Vaccine development would be greatly facilitated by a new approach, in which nanoscale modules (Ag, adjuvant, and carrier) are assembled into units that are optimized for stimulating immune responses to a specific pathogen. Toward that goal, we formulated biodegradable nanoparticles loaded with Ag and surface modified with the pathogen-associated molecular pattern CpG oligodeoxynucleotides.

Spatiotemporal control over molecular delivery and cellular encapsulation from electropolymerized micro- and nanopatterned surfaces.

Bioactive, patterned micro- and nanoscale surfaces that can be spatially engineered for three-dimensional ligand presentation and sustained release of signaling molecules represent a critical advance for the development of next-generation diagnostic and therapeutic devices. Lithography is ideally suited to patterning such surfaces due to its precise, easily scalable, high-throughput nature; however, to date polymers patterned by these techniques have not demonstrated the capacity for sustained release of bioactive agents. We demonstrate here a class of lithographically-defined, electropolymerized polymers with monodisperse micro- and nanopatterned features capable of sustained release of bioactive drugs and proteins.

Biomimetic approaches to modulating the T cell immune response with nano- and micro- particles.

Modulating immune responses to pathogen invasion and even tumors is a major goal in immunotherapy. T cells play a central role in these responses. Progress towards that goal is accomplished by stimulating the antigen-specific T cell immune response in vivo through active immunization, or by re-transfer of large numbers of T cells expanded outside the body in a process called adoptive immunotherapy.

Inflammasome-activating nanoparticles as modular systems for optimizing vaccine efficacy.

Innate immune system activation is a critical step in the initiation of an effective adaptive immune response; therefore, activation of a class of innate pathogen receptors called pattern recognition receptors (PRR) is a central feature of many adjuvant systems. It has recently been shown that one member of an intracellular PRR, the NLRP3 inflammasome, is activated by a number of classical adjuvants including aluminum hydroxide and saponins [Eisenbarth SC, Colegio OR, O'Connor W, Sutterwala FS, Flavell RA. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants.

Design opportunities for actively targeted nanoparticle vaccines.

Vaccines for many infectious diseases are poorly developed or simply unavailable. There are significant technological and practical design issues that contribute to this problem; thus, a solution to the vaccine problem will require a systematic approach to test the multiple variables that are required to address each of the design challenges. Nanoparticle technology is an attractive methodology for optimizing vaccine development because design variables can be tested individually or in combination.