Oligomer-Nanoparticle Release from PLA Bioplastics Catalyzed by Gut Enzymes and Its Acute Inflammatory Effect

<title>Abstract</title> Although the risks of microplastics in environmental exposure and human health are being increasingly studied, little is known about the behavior of “eco-friendly” bioplastics in humans, especially their effects on our gastrointestinal tract. Here we demonstrate that enzymatic hydrolysis of bio-based polylactic acid (PLA) microplastics rapidly generates an excess of nanoplastic particles by competing for triglyceride-degrading lipase during gastrointestinal processes. These tiny nanoparticles are oligomers formed by hydrophobic-driven self-aggregation, and upon exposure the oligomers and their associated nanoparticles can bioaccumulate in <italic>in vitro</italic> and several <italic>in vivo</italic> organs, including the liver, intestine, and even in the brain. Severe intestinal damage and inflammation are also observed, the toxic effect of which is mostly pronounced from hydrolyzed oligomer products. Furthermore, the oligomers’ potential protein target screening using large scale pharmacophore model reveals that oligomers can interact with matrix metallopeptidase 12 protein (MMP12), which is further validated using protein binding assay. A close mechanistic study reveals high binding affinity of oligomers to the catalytic zinc ion finger domain, leading to MMP12 inactivation and mediating the adverse bowel inflammatory effect following PLA oligomer exposure. Since biodegradable plastics are highly proposed as one solution for the global plastic problem, understanding the gastrointestinal fate and toxicity of bioplastics, will provide ground-breaking data on bioplastics as a substantial risk to human health.