Toxicity Differences Between Microplastics and Nanoplastics in Organs: From Molecular Mechanisms to Potential Therapeutic Strategies

ABSTRACT Microplastics (MPs, < 5 mm) and nanoplastics (NPs, < 1 μm) have become ubiquitous environmental contaminants. They pose emerging risks to human health. These particles enter the body via ingestion or inhalation. They then accumulate in organs such as the intestine, liver, kidney, lung, and brain, leading to organ‐specific toxicity. Particle size critically determines their bioavailability, cellular uptake, and barrier permeability. Consequently, size shapes their toxicological mechanisms. There is a lack of globally harmonized nanoparticle sizing standards. Therefore, this review primarily discusses NPs defined as particles < 1 μm. This is the most commonly adopted definition in the toxicological literature. However, we acknowledge the potential biological differences between “ultra‐small NPs” (< 100 nm) and “sub‐micron particles” (100–1000 nm). These differences are briefly addressed in the relevant sections. This review summarizes recent progress on the size‐dependent toxicity of MPs and NPs. Owing to their smaller size and higher surface area, NPs readily cross biological barriers. They localize to organelles and trigger mitochondrial dysfunction, oxidative stress, ferroptosis, and inflammatory activation. In contrast, larger MPs mainly induce physical and immune‐mediated injury. They cause tight‐junction disruption, macrophage activation, and yes‐associated protein (YAP)‐dependent mechanotransduction. This leads to chronic inflammation, metabolic reprogramming, and fibrosis. Distinct organ‐specific patterns emerge. YAP‐driven metabolic disturbance predominates in the intestine, whereas oxidative and inflammatory cascades are central to hepatic and renal injury. The intestine acts as a pivotal hub for systemic toxicity through the gut–liver, gut–brain, and gut–kidney axes. Targeted interventions—including ferroptosis inhibitors, engineered probiotics, and multi‐target natural compounds—offer promising mitigation strategies. Collectively, understanding size‐dependent mechanisms provides a foundation for precision toxicology and health‐risk assessment of plastic pollution.