Micro- and Nanoplastic Co-exposure: Mechanisms, Modulating Factors, and Context-Dependent Antagonistic and Synergistic Toxicity

Micro- and Nanoplastic (MP and NP) are now recognized as biologically active contaminants that interact with cells, tissues, and other pollutants present in the environment. Most toxicity studies have looked at single plastic particles alone, so we still know little about what happens when MP and NP are present together, as they usually are in real life. This review focuses on one central question: when do MP and NP interactions weaken each other’s toxic effects (antagonism), and when do they add up or amplify each other (synergism)? To provide toxicological clarity, this synthesis explicitly categorizes the evidence base into three distinct classes: (i) direct MP + NP joint particle exposures, (ii) plastic particle co-exposure with non-plastic chemical co-contaminants operating via vector transport, and (iii) single-particle toxicological foundations utilized strictly to establish baseline cellular mechanisms. We examine how particle uptake, movement through the body, breakdown, tissue distribution, and cell-level interactions are shaped by particle size, concentration, the size ratio between MP and NP, polymer type, surface chemistry, particle shape, and the physiological setting. At the cellular level, combined exposure affects shared pathways, including oxidative stress, mitochondrial damage, weakened antioxidant defenses, Nrf2 and NF-κB signaling, NLRP3 inflammasome activation, lysosomal and autophagy disruption, DNA damage, and cell death (apoptosis and pyroptosis). We also evaluate the ‘Trojan horse’ effect, where plastic particles carry other harmful substances into cells, contrasting contaminant loading against competing sink mechanisms such as extracellular desorption, heteroaggregation, and bio-corona masking. Rather than representing a universal deterministic rule, the antagonistic-to-synergistic transition is reframed as a context-dependent working hypothesis governed by multi-dimensional variables: particle size ratio, mass vs. particle-number dosimetry, polymer composition, surface functionalization, environmental weathering, exposure duration, and physiological tissue repair capacity. Antagonism can occur through competitive binding, particle sequestration, reduced bioavailability, or cellular adaptation, while synergism becomes more likely as particle load increases, smaller particles are taken up more easily, particle-size combinations become unfavorable, and cell defense systems become overwhelmed. Susceptibility also differs across the intestine, liver, spleen, and brain, and can be influenced by age, sex, and health status. Overall, this review argues that the antagonistic-to-synergistic transition is the central pattern in MP and NP toxicology, requiring standardized dosimetry, realistic mixture exposures, PBTK modeling, and human-relevant organoid platforms to evaluate long-term cumulative health risks.