Obesity is becoming a serious global public health challenge. Its population has grown rapidly over the past half century and is expected to exceed 2.5 billion adults by 2025. Obesity can induce or accelerate many diseases, such as type 2 diabetes, cardiovascular disease, osteoarthritis and malignant tumors, which constitute the major spectrum of non-infectious diseases and important causes of death in modern society.
Systemic aseptic inflammatory state is an important feature of metabolic diseases such as obesity, and it can occur in multiple tissues, especially white adipose tissue (WAT). Obesity induces a series of pathological events in WAT, leading to chronic inflammation, including macrophage infiltration, mitochondrial dysfunction, endoplasmic reticulum stress, etc. The inflammatory state further impairs the functions of glucose uptake and lipid storage in WAT. As a result, excess lipids were deposited in liver, muscle, etc., which led to lipid toxicity and increased insulin resistance, forming a positive feedback loop and exacerbating inflammation in WAT. From this perspective, obesity is widely considered to be a chronic inflammatory disease, with the potential to reduce the risk of associated metabolic disorders by improving the inflammatory state. Despite the great success of many anti-inflammatory drugs, there is still a lack of drugs that can effectively combat chronic inflammation and improve metabolism in obesity. Therefore, the discovery of new inflammatory factors in obesity is an important prerequisite for exploring new ways to suppress chronic inflammation.
In recent years, it has been found that circulating cell free nucleic acids (cfNAs) are a new type of inflammatory factors. cfNAs constitute complex, according to the types of nucleic acid can be divided into two categories: free DNA (cfDNA) and free RNA (cfRNA). They are derived from necrotic and apoptotic cells, viruses, intestinal bacteria, etc., and can activate inflammatory networks by binding to specific toll-like receptors (TLR) and participate in the regulation of innate immune response. When the TLR signaling pathway is over-activated, it can aggravate systemic lupus erythematosus, inflammatory bowel disease, rheumatoid arthritis and other diseases.
Animal studies have confirmed that a variety of cationic polymers or nanoparticles as scavengers can improve a number of acute inflammatory diseases, such as acute liver failure, bacterial sepsis, and so on. However, their role in metabolic diseases characterized by chronic inflammation remains unknown. Polyamides (PAMAM) are classical dendritic macromolecular polymers with a symmetrical and highly branched molecular structure and the presence of internal cavities. In recent years, it has been widely used as a representative polymer in nanomedicine. In addition to acting as a drug or gene carrier, cationic PAMAM also has the function of neutralizing negatively charged pathogens such as cfDNA.
On November 29, 2022, Professor Qiang's team from Columbia University and Professor Kam W. Leong's team, Huang Baoding, Wan Qianfen, Dr. Li Tianyu and other researchers published a research paper on obesity-related metabolic inflammation and its treatment on Biomaterials: Polycationic PAMAM ameliorates obesity-associated chronic inflammation and focal adiposity. The study showed that significantly elevated cfRNA in the plasma of diet-induced obese mice activated TLR3 and 8 receptors, which are involved in the formation of chronic inflammation in the body. The use of the 3rd generation PAMAM (PG3) can effectively clear cfRNA, reduce the inflammatory state of the body through the co-regulation of pro-inflammatory and anti-inflammatory factors, and show weight loss effect while improving metabolism. In order to further improve the convertibility, the research team then took advantage of the non-toxicity, low immunogenicity and good drug loading performance of human blood albumin (HSA) to develop HSA-PG3 sustained release nanoparticles suitable for local application. HSA-PG3 demonstrated precise local fat localization and significant targeted weight loss. It completely avoids entering the blood circulation and other tissues, thus increasing safety as much as possible. This study not only deepens the understanding of the mechanism of cfRNA's involvement in metabolic inflammation, but also opens up a new strategy for improving metabolic inflammation and focal obesity by using positive materials.
