Engineered metabolite-based nanoparticles for immunomodulation of macrophages to treat obesity - Project Summary Obesity can be characterized as a multifactorial pathology and a chronic low-grade inflammatory disease that is accompanied by metabolic dysregulation. More than two billion people worldwide are obese, with approximately 167 million new adults and children becoming overweight or obese by the end of 2025. Obesity is of critical concern due to its wide-reaching associations with metabolic diseases, including non-alcoholic fatty liver disease, cardiovascular disease, and type II diabetes. Current obesity treatments can be broadly categorized into lifestyle modifications and medical interventions, including surgery and pharmacotherapy. Despite the recent success of anti-obesity medications, they still suffer from limitations, including frequent dosing requirements, high cost (e.g., GLP-1 agonists), non-responder issues, and potential for serious side effects. Several studies have suggested that an imbalance in the ratio of M2-to-M1 macrophages in adipose tissue is associated with obesity, where newly recruited macrophages tend to adopt a “pro-inflammatory” M1-like phenotype compared to tissue-resident macrophages that tend to have an “anti-inflammatory” M2-like phenotype. Our long-term goal is to develop a simple and broad-acting nanoparticle (NP)-based immunotherapy to achieve sustained improvements in local and systemic inflammation, restore the M2/M1 balance in adipose tissue, restore metabolic health, and limit comorbidity development in obese patients. NPs offer an effective strategy to modulate macrophage polarization through the delivery of bioactive substances, balancing the low-grade inflammatory response, while enabling local retention and controlled release properties. However, effective delivery with NPs often requires high doses and frequent administration due to loading/encapsulation/drug retention issues. Through an innovative approach, our lab has developed IMPRINT-NPs (ImmunoModulatory Particles for Reversing INflammation and phenotype Transformation) prepared from biodegradable polyesters synthesized from endogenously produced bioactive metabolites. Compared to traditional NP approaches, IMPRINT-NPs are unique as they are ‘drug-free’ and their activity depends on their composition rather than encapsulated agents. Our strong preliminary data showed that metabolite-based polymeric NPs could induce potent anti-inflammatory responses, repolarize M1-to-M2 phenotypes, induce fat browning, and enhance sensitivity while reducing weight gain in a high-fat diet (HFD)-induced obesity mouse model. Herein, we propose to evaluate the immunomodulatory responses of metabolite-based polymers and IMPRINT-NPs for the modulation of macrophages and adipocytes, focusing on structure-function relationships and mechanistic investigations (Aim 1). Next, in Aim 2, we will examine the in vivo toxicity, ability of IMPRINT-NPs to modulate local and systemic responses, macrophage polarization, adipose tissue function, and obesity outcomes. The dosing and timing effects of IMPRINT-NPs will be optimized and mechanistically evaluated. Finally, their efficacy will be explored in combination with a clinically relevant GLP-1 receptor agonist to assess potential efficacy enhancements.
