The immune system is the key target for vaccines and immunotherapeutic approaches aimed at blunting infectious diseases, cancer, autoimmunity, and implant rejection. However, systemwide immunomodulation is undesirable due to the severe side effects that typically accompany such strategies. In order to circumvent these undesired, harmful effects, scientists have turned to tailorable biomaterials that can achieve localized, potent release of immune-modulating agents. Specifically, "stimuli-responsive" biomaterials hold a strong promise for delivery of immunotherapeutic agents to the disease site or disease-relevant tissues with high spatial and temporal accuracy. This review provides an overview of stimuli-responsive biomaterials used for targeted immunomodulation. Stimuli-responsive or "environmentally responsive" materials are customized to specifically react to changes in pH, temperature, enzymes, redox environment, photo-stimulation, molecule-binding, magnetic fields, ultrasound-stimulation, and electric fields. Moreover, the latest generation of this class of materials incorporates elements that allow for response to multiple stimuli. These developments, and other stimuli-responsive materials that are on the horizon, are discussed in the context of controlling immune responses.

Use of biomaterials to spatiotemporally control the activation of immune cells is at the forefront of biomedical engineering research. As more biomaterial strategies are employed for immunomodulation, understanding the immunogenicity of biodegradable materials and their byproducts is paramount in tailoring systems for immune activation or suppression. Poly(D,L-lactic-co-glycolic acid) (PLGA), one of the most commonly studied polymers in tissue engineering and drug delivery, has been previously described on one hand as an immune adjuvant, and on the other as a nonactivating material. In this study, the effect of PLGA microparticles (MPs) on the maturation status of murine bone marrow-derived dendritic cells (DCs), the primary initiators of adaptive immunity, was investigated to decipher the immunomodulatory properties of this biomaterial. Treatment of bone marrow-derived DCs from C57BL/6 mice with PLGA MPs led to a time dependent decrease in the maturation level of these cells, as quantified by decreased expression of the positive stimulatory molecules MHCII, CD80, and CD86 as well as the ability to resist maturation following challenge with lipopolysaccharide (LPS). Moreover, this immunosuppression was dependent on the molecular weight of the PLGA used to fabricate the MPs, as higher molecular weight polymers required longer incubation to produce comparable dampening of maturation molecules. These phenomena were correlated to an increase in lactic acid both intracellularly and extracellularly during DC/PLGA MP coculture, which is postulated to be the primary agent behind the observed immune inhibition. This hypothesis is supported by our results demonstrating that resistance to LPS stimulation may be due to the ability of PLGA MP-derived lactic acid to inhibit the phosphorylation of TAK1 and therefore prevent NF-κB activation. This work is significant as it begins to elucidate how PLGA, a prominent biomaterial with broad applications ranging from tissue engineering to pharmaceutics, could modulate the local immune environment and offers insight on engineering PLGA to exploit its evolving immunogenicity.

In pursuit of a preventive therapeutic for maternal autoantibody-related (MAR) autism, we assessed the toxicity, biodistribution, and clearance of a MAR specific peptide-functionalized dextran iron oxide nanoparticle system in pregnant murine dams. We previously synthesized ~15 nm citrate-coated dextran iron oxide nanoparticles (DIONPs), surface-modified with polyethylene glycol and MAR peptides to produce systems for nanoparticle-based autoantibody reception and entrapments (SNAREs). First, we investigated their immunogenicity and MAR lactate dehydrogenase B antibody uptake in murine serum in vitro. To assess biodistribution and toxicity, as well as systemic effects, we performed in vivo clinical and post mortem pathological evaluations. We observed minimal production of inflammatory cytokines-interleukin 10 (IL-10) and IL-12 following in vitro exposure of macrophages to SNAREs. We established the maximum tolerated dose of SNAREs to be 150 mg/kg at which deposition of iron was evident in the liver and lungs by histology and magnetic resonance imaging but no concurrent evidence of liver toxicity or lung infarction was detected. Further, SNAREs exhibited slower clearance from the maternal blood in pregnant dams compared to DIONPs based on serum total iron concentration. These findings demonstrated that the SNAREs have a prolonged presence in the blood and are safe for use in pregnant mice as evidenced by no associated organ damage, failure, inflammation, and fetal mortality. Determination of the MTD dose sets the basis for future studies investigating the efficacy of our nanoparticle formulation in a MAR autism mouse model.

Introduction: Autism Spectrum Disorder (ASD) comprises a range of developmental disorders diagnosed in early childhood, where their ability to communicate and interact are impaired. In the U.S., an estimated 1 in 59 children1 is born with ASD and the economic burden is a staggering $268 billion per year2. Current therapies are post-symptomatic and include behavioral interventions or symptom-derived pharmacological treatments. Recently, the Van De Water group discovered that about a quarter of ASD cases are caused by maternal autoantibodies (autoAbs) that can hinder normal neurodevelopment in the fetus. Moreover, they elucidated the seven proteins targeted by these autoAbs in the fetal brain, including lactate dehydrogenase A and B (LDHA, LDHB)3. Herein, we aim to develop a System for Nanoparticle-based Autoantibody Retention and Entrapment (SNARE) prophylactic as a biomagnetic trap-for sequestration of disease-propagating Maternal Autoantibody-Related (MAR) autoAbs. Our central hypothesis is that upon intravenous injection, the iron oxide NPs surface-conjugated with autoantigens will circulate throughout the maternal vasculature, and specifically ligate MAR autoAbs, thereby limiting antibody (Ab) transport across the placenta and preventing MAR autism. Currently, investigative aims are to synthesize SNAREs, assess Ab binding capacity, cytotoxicity and immunogenicity in vitro, as well as determine in vivo distribution and maximum tolerated dose.