Respiratory risks of microplastics and nanoplastics: Where? What? How?

Abstract

Microplastics (MPs) and nanoplastics (NPs) are pervasive and persistent environmental pollutants raising growing concerns regarding their potential hazards to human respiratory health. This review systematically summarizes current epidemiological evidence and experimental findings concerning the respiratory toxicity of MPs and NPs. Exposure to these particles is associated with various pulmonary disorders, including pneumonia, chronic obstructive pulmonary disease, asthma, and other pathological lung injury. At the molecular level, MP- and NP-induced toxicity primarily involves oxidative stress, leading to mitochondrial dysfunction and endoplasmic reticulum stress. This oxidative damage triggers diverse forms of cell death, such as apoptosis, pyroptosis, ferroptosis, and autophagy. Furthermore, MPs and NPs induce pulmonary inflammation, disrupt the integrity of the alveolar-capillary barrier, promote pulmonary fibrosis, and cause DNA damage, mainly via oxidative stress pathways. This review also identifies critical directions for future research on the respiratory toxicity of MPs and NPs. Overall, this review highlights the respiratory health risks associated with MPs and NPs, emphasizing mechanisms involving oxidative stress, inflammation, and fibrosis, and underscores the urgent need for further investigation. It provides essential toxicological evidence and insights that could inform the development of effective protective strategies.

Graphical abstract

Public summary

• •Review focuses on “where-what-how-future” of microplastics (MPs) and nanoplastics (NPs) on respiratory system.
• •MPs and NPs are airborne pollutants, indoor concentrations > outdoor concentrations.
• •Critical review of the respiratory toxicity and Trojan horse effect of different MPs and NPs.
• •Oxidative stress and inflammation are important toxic mechanisms of MPs and NPs.
• •Urgent to clarify respiratory risks of MPs and NPs related to environment and develop protective strategies.

Introduction

Exposure to microplastics (MPs) and nanoplastics (NPs) has become a growing global public health concern.¹ The term “microplastics” was first introduced by Thompson et al. in 2004.² MPs range in size from 1 μm to 5 mm, whereas NPs are defined as particles smaller than 1 μm.³ Common types of MPs and NPs include polyethylene (PE), PE terephthalate (PET), polypropylene (PP), polyvinyl chloride (PVC), polystyrene (PS), polyamide (PA), polylactic acid (PLA), polycarbonate (PC), and other polymers. MPs exist in various forms, including fibers, fragments, particles, and films, while NPs primarily include particles and fragments (Figure 1A). Over the past half-century, plastics have been extensively used in industry, agriculture, and daily life due to their high versatility, durability, and low cost, resulting in cumulative global production of approximately 9 billion tons. Annual plastic production continues to rise, increasing from 1.5 million tons in the 1950s to 430 million tons in 2024 (Figure 1B). Global plastic production is projected to double by mid-century.^4,5 Due to their non-biodegradable nature, only about 10% of plastics are recycled, and the remainder is incinerated, landfilled, or released into the environment, causing severe white pollution and generating MPs and NPs.⁴ Initially recognized primarily as marine pollutants, recent studies indicate that MPs and NPs have dispersed globally due to their small size and high mobility, permeating nearly every region of the Earth.³ They have been detected even in remote areas (Figure 1C) such as the Arctic,^6,7 Antarctic,⁸ Mount Everest,⁹ and Alpine glaciers,¹⁰ posing significant risks to both environmental and human health.

Figure 1.

A panoramic view of plastics

(A) Comparison of MPs and NPs.

(B) Annual global production of plastic products. Data reference: Plastics Europe.

(C) Timeline of discovery and policy regarding MPs. EU, European Union; UNEP, United Nations Environment Program.

MPs and NPs represent a significant risk to human health.^11,12 They have been detected in human carotid artery plaques, where they contribute to an increased risk of cardiovascular disease.¹³ Moreover, NPs are capable of crossing the placental barrier, blood-testis barrier, and blood-brain barrier, leading to reproductive toxicity and neurotoxicity (Figure 1C).^{14,15,16,17,18} Furthermore, environmental pollution is strongly associated with the development of respiratory diseases.¹⁹ Recent studies have shown that the abundance of MPs and NPs in lung tissue significantly exceeds the levels in other organs, indicating that the lungs are the primary target organ for MPs and NPs.^20,21,22 Epidemiological studies confirm that exposure to MPs and NPs increases the risk of respiratory diseases.^23,24 Toxicological models combined with high-throughput sequencing further indicate that MPs and NPs primarily induce respiratory diseases.²⁵ Therefore, a systematic review of the respiratory toxicity of MPs and NPs is crucial for understanding health risks, identifying key hazard factors, and developing scientifically grounded preventive strategies.

Over the past 5 years, numerous reviews have provided valuable insights into the overall health effects of MPs and NPs, establishing a foundation for understanding systemic toxicity and guiding future research.^{26,27,28,29,30} While previous reviews are informative, many adopt a broad perspective, which does not adequately address the specific respiratory effects of MPs and NPs. In addition, although the emerging literature on the potential respiratory health risks of MPs and NPs has laid the foundation for the field in recent years,^{31,32,33,34,35,36,37} rapid progress in this field has generated an expanding body of evidence, and there are several key interfaces and future directions that require clarification. This review constructs a complete chain from “where-what-how-future,” integrating perspectives from environmental science, toxicology, and public health to provide a more comprehensive synthesis at the current stage. It emphasizes critical assessment and guidance for future directions while focusing on the systematization and visualization of knowledge. It first examines the generation, distribution, and human exposure pathways of MPs and NPs (where). Next, it compiles and evaluates experimental and epidemiological findings from the past decade regarding respiratory toxicity in humans, mammals, and birds (what). It then explores the key molecular mechanisms through which MPs and NPs impact the respiratory system (how). Finally, the review identifies major research gaps that warrant further study.

Where: Sources of MPs and NPs and their exposure pathways in the respiratory system

Environmental sources of MPs and NPs are typically classified as either primary or secondary. Secondary MPs and NPs originate from fragmentation of larger plastic debris via physical and chemical processes, including abrasion, ultraviolet radiation, hydrolysis, and biodegradation. Primary MPs and NPs are directly introduced into the environment from sources such as cosmetic products, synthetic textiles, cleaning agents, and toothpaste (Figure 2).³⁸ Currently, electron microscopy, Fourier transform infrared (FTIR) spectroscopy, Raman spectroscopy, and pyrolysis-gas chromatography/mass spectrometry (Py-GC/MS) are the primary techniques employed to detect and identify MPs and NPs.³⁹ However, existing detection methods for environmental MPs and NPs remain largely qualitative or semi-quantitative. Although these techniques can confirm the presence of plastic particles, accurately quantifying contributions from individual sources remains challenging. Furthermore, knowledge about fragmentation rates of plastics in the environment, influencing factors, and resulting particle size distributions remains limited. These uncertainties complicate the assessment of control measure effectiveness. Consequently, predicting the impact of banning specific product categories on environmental levels and human exposure remains difficult.

Figure 2.

MP and NP pollution: Sources, circulation, and exposure pathways

Marine and freshwater environments are major reservoirs of MPs and NPs (38–234 particles/m³),^2,40,41 with substantial quantities identified in water columns, riverbeds, and sediments.⁴² Crucially, these particles accumulate in various aquatic organisms, ranging from zooplankton and invertebrates to vertebrates (Figure 2).⁴³ MPs and NPs are also prevalent in soil matrices worldwide (350–1,640 particles/kg) originating from plastic waste associated with industrial, agricultural, and domestic activities, agricultural runoff, sewage sludge application, landfill leachate, and atmospheric deposition.^41,44,45 MPs and NPs may also accumulate within and transfer among plants (Figure 2).^46,47 Furthermore, substantial amounts of MPs and NPs exist in the atmosphere,⁴⁸ primarily derived from synthetic textiles, oceans, particulate matter, tire wear, waste disposal sites, smoking, and agricultural soil dust.^{49,50,51,52,53} Airborne MPs and NPs predominantly exist as fibers and irregular particles, with common polymer types including PET, PE, PP, and PS. Due to detection limitations, most reported airborne plastic particles range from 1 to 100 μm in size. However, Py-GC/MS analyses have confirmed the presence of NPs smaller than 1 μm (Table S1). The distribution and deposition of these airborne particles are influenced by both human activities and meteorological conditions. Studies have demonstrated that MPs and NPs in indoor air significantly increase human exposure risk,^52,54,55 with indoor concentrations (1–1,583 particles/m³ or 0–25,600 particles/m²/day) typically higher than outdoor levels (0–224 particles/m³ or 4–925 particles/m²/day) (Table S1). This difference likely results from the shedding of synthetic fibers from clothing, furniture, and household dust. Therefore, the ubiquitous presence of MPs and NPs poses a serious threat to ecosystems and human health. Notably, methodological inconsistencies in sampling and analysis contribute to substantial variability in reported MPs concentrations, hindering comparisons of respiratory toxicity across studies. Moreover, inherent limitations in current sampling and detection methods, particularly for NPs, likely result in significant underestimation of their actual environmental abundance and human exposure.

MPs and NPs enter the human body through multiple pathways (Figure 2), including drinking water, food ingestion, inhalation, and skin contact. In addition, MPs and NPs can accumulate and propagate through the food chain.⁴⁶ The respiratory system is particularly susceptible to exposure. Compared with other exposure routes, inhalation, especially indoors, represents a major pathway for MP and NP intake.^56,57 Notably, MPs and NPs ingested via other routes may also reach the lungs through systemic circulation.^58,59,60 It is estimated that individuals are exposed to approximately 74,000–121,000 MP particles per year (8.32 ng/kg/day), with nearly half of this exposure attributed to inhalation.^61,62 Inhalable particulate matter entering through the nostrils or oral cavity can deposit within the respiratory tract and lungs via inertial impaction, gravitational sedimentation, and Brownian diffusion.⁶³ Typically, MPs with diameters smaller than 10 μm can reach the bronchi, whereas those below than 2.5 μm can penetrate deeper into the alveolar regions (Figure 1A).⁶⁴ Notably, plastic fibers substantially larger than these sizes have also been detected in lung tissues.^23,24 Our current understanding of respiratory clearance mechanisms for MPs and NPs remains limited. Particle size and shape affect physical clearance. Macrophages show maximal phagocytic and adhesive activity toward particles around 2–3 μm in diameter.⁶⁵ Additionally, chemical clearance mechanisms may exert dual effects. Pulmonary surfactants can promote the release of toxic substances from MPs,⁶⁶ enhancing their bioavailability to lung cells. Consequently, MPs and NPs entering the alveoli are difficult to remove,⁶⁷ posing persistent and long-term health risks.

What: Adverse effects of MPs and NPs on the respiratory system

Human evidence

Accumulation

MPs and NPs have recently been identified in human lung tissue and bronchoalveolar lavage fluid (Table 1; Figure 3A). The predominant types identified are PP and PE, with particle sizes typically ranging from 1 to 1,000 μm. Reported mean concentrations of MPs and NPs range from 0.56 to 6.00 particles/g in lung tissue and 0.01 to 407.70 particles/mL in alveolar fluid. Notably, Momeni et al. and Zhang et al. demonstrated that smaller MPs exhibit a greater capacity to penetrate lung cells than larger particles.^70,80 These findings provide direct evidence of MP and NP accumulation in the human respiratory system and highlight their potential for cellular infiltration and adverse effects. However, current studies cannot accurately determine the sources of MPs detected in the respiratory system. In addition, most bronchoalveolar lavage fluid and lung tissue samples analyzed to date were obtained from patients with various diseases, potentially influencing plastic deposition in the respiratory system. Furthermore, limitations in detection technologies have restricted the direct identification of NPs in the human respiratory tract. Owing to the widespread presence of MPs and NPs, many studies lack rigorous negative controls and standardized sampling and detection protocols, introducing uncertainty into reported results.

Table 1.

Epidemiological studies investigating respiratory toxicity following MP and NP exposure

Time	Type	Concentration	Size	Source	Toxic effects	Reference
2022	PP, PET	1.42 ± 1.50 particles/g	4–88 μm	lung tissue	–	Jenner et al.68
2023	PP, PE, PS	6.00 (6.34) particles/g	–	lung tissue	–	Jianpeng et al.69
2023	PU, BR, CPE	25.86 ± 23.97 particles/mL	20–100 μm	bronchoalveolar lavage fluid	–	Dris et al.53
2025	PS, PU, FEP, PFA, PE	0.73 (0.64) particles/mL	11–1,135 μm	bronchoalveolar lavage fluid	–	Momeni et al.70
2025	PP, PC, PA, PVC	1.38 ± 0.69 particles/mL	–	bronchoalveolar lavage fluid	–	Firouzsalari et al.71
2025	PE, PP, PS	0.42 ± 0.36 particles/mL	20–100 μm	bronchoalveolar lavage fluid	–	Jahedi et al.72
2021	PE, PP	0.56 ± 0.53 particles/g	8.12–16.8 μm	lung tissue	emphysema, pneumonia	Amato-Lourenço et al.73
2022	PA	0.09 ± 0.02 particles/mL	1,580–9,960 μm	bronchoalveolar lavage fluid	growth of pathological microbes, pulmonary dysfunction	Baeza-Martínez et al.74
2023	PP, PE, PET	0.43 ± 0.28 particles/mL	1–20 μm	bronchoalveolar lavage fluid	community-acquired pneumonia	Chen et al.23
2023	Fragments	0.01 (0.02) particles/mL	35–1,020 μm	bronchoalveolar lavage fluid	bronchiectasis, focal infiltration	Uogintė et al.75
2023	PP, PET, PS	4.31 ± 5.11 particles/g	20–100 μm	lung tissue	reduction of platelets, fibrinogen, and direct bilirubin	Wang et al.76
2024	PA, PET, PVC, PU	–	4.19–792.00 μm	bronchoalveolar lavage	pulmonary fibrosis	Özgen Alpaydin et al.24
2025	PVC, PS, PET, PP, PMMA	407.70 (1163) particles/mL	1.21–261.7 μm	bronchoalveolar lavage fluid	elevated C-reactive protein	Tokito et al.77
2025	PVC, PE, PS, PP	4.49 ± 4.75 μg/g	–	bronchoalveolar lavage fluid	exacerbation of community-acquired pneumonia	Liu et al.78
2025	PET, PS, PC, PLA, PA, MMA	253.77 ± 105.40 μg/g	–	lung tissue	COPD	Wei et al.79

Concentration: mean ± SD or median (interquartile range). PU, polyurethane; FEP, fluorinated ethylene propylene; PFA, perfluoroalkoxy; BR, butadiene rubber; CPE, chlorinated polyethylene; PMMA, polymethyl methacrylate.

Figure 3.

Impact of MPs and NPs on the respiratory system

(A) Epidemiological evidence of the effects of MPs on the human respiratory system.

(B) Respiratory toxicity of MPs and NPs in animals.

(C) Respiratory toxicity of MPs and NPs in cells.

(D) Combined toxic effects of MPs and NPs with other pollutants in the respiratory system.

PHA, polyhydroxyalkanoate; PES, polyethersulfone.

Epidemiological evidence of respiratory toxicity from MPs

Several epidemiological studies have demonstrated a positive association between MP exposure and respiratory diseases. Research by Chen et al.,²³ Baeza-Martínez et al.,⁷⁴ and Amato-Lourenço et al.⁷³ has linked MP exposure to an increased risk of pneumonia. In addition, exposure to these particles has been associated with reduced lung function, emphysema, and an elevated risk of bronchiectasis.⁷⁵ Further studies suggest that MP exposure may also contribute to the development of pulmonary fibrosis and lung cancer.^24,76,81 Recent evidence indicates that MP exposure can increase C-reactive protein levels and exacerbate symptoms in patients with community-acquired pneumonia.^77,78 Furthermore, exposure to MPs has been linked to the development and progression of chronic obstructive pulmonary disease (COPD).⁷⁹ Collectively, these findings support the conclusion that MP exposure can induce respiratory toxicity in humans (Table 1; Figure 3A). However, most existing population-based epidemiological studies on MPs involve small sample sizes, limiting causal interpretation. Future research should prioritize large-scale cohort studies to systematically evaluate the respiratory effects of MPs and NPs with different shapes, sizes, and compositions. Moreover, existing studies rarely differentiate respiratory toxicity according to plastic type, shape, and size. MPs and NPs also frequently act as carriers for other pollutants, including heavy metals and persistent organic contaminants, complicating assessment of their independent roles in respiratory diseases. In addition, evidence from vulnerable populations, such as children, older-adult occupational groups, and patients with pre-existing respiratory conditions, remains scarce, representing a significant public health concern.

Animal studies

Studies have confirmed the presence of MPs in the lung tissues of domestic and fetal pigs from natural environments (Table S2). Reported concentrations were 180 particles/g (size range: 20.34–916.36 μm) in domestic pigs and 97 particles/g (size range: 20.34–501.49 μm) in fetal pigs.⁸² MPs concentrations in the lung tissues of mammals from aquatic environments ranged from 0.14 to 180 particles/g.^21,83 NPs also accumulate in mammalian lung tissue. In one study, female ICR mice orally exposed to NPs at 30 mg/kg body weight for 35 days exhibited NP accumulation in lung tissue at a concentration of 103.70 ± 14.41 μg/g.⁸⁴ Tokunaga et al.⁸⁵ detected MPs in the lungs of wild birds, including Columba livia, Milvus migrans, and Hirundo rustica. Similarly, Wang et al.⁸⁶ identified 32 different MP and NP types in wild bird lungs (Table S2). These findings clearly demonstrate that MPs and NPs accumulate in mammalian and avian lung tissues after environmental or experimental exposure.

Mice and rat studies

Laboratory studies (details are provided in the supplemental information) indicate that MPs and NPs induce significant pulmonary toxicity in rodents (Table 2; Figure 3B). In mice, MP and NP exposure consistently causes structural lung damage and inflammation, along with elevated inflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and IL-1β, and activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome.^87,103,125 The gut-lung axis also appears to contribute to MP- and NP-induced pulmonary injury, as these particles disrupt the gut microbiota, increase lactate production, and exacerbate lung injury through the HIF1α/PTBP1 signaling pathway.^89,126 Furthermore, MPs and NPs cause notable oxidative stress (increased ROS/MDA and decreased SOD/CAT/GSH-Px),^67,88 mitochondrial dysfunction,⁹³ and endoplasmic reticulum stress (ERs),^67,92 indicated by upregulated C/EBP homologous protein (CHOP), XBP1s, p-IRE1, and p-PERK expression. Moreover, MPs and NPs impair lung function in mice,^{107,111,116,127} including cell death, fibrosis (collagen deposition), lung barrier integrity, and restrictive ventilatory dysfunction. Rats exposed to MPs and NPs exhibit dose-dependent lung injury, inflammation, emphysema-like changes, airway hyperresponsiveness, and pulmonary dysfunction,^{117,118,119,122} demonstrating a similar pathogenic mechanisms across species.

Table 2.

Summary of MPs and NPs in respiratory toxicity studies in vivo

Object	Size	Exposure	Dose	Time	Toxic effects	Reference
Male C57BL/6 mice	PS: 0.5, 5 μm	i.g./daily	0.5 mg/mice	56 days	lung index, inflammation, lung injury	Zhang et al.87
Female C57BL/6 mice	PS, PS-COOH: 1–5 μm, 10–20 μm	i.n./daily	40 mg/kg	21 days	apoptosis, inflammation, oxidative stress, collagen deposition, fibrosis, 1–5 μm > 10–20 μm	Cao et al.88
Male C57BL/6 mice	PS: 50–100 nm	i.t./thrice per week	15 mg/kg	28 days	Gut-lung axis, lung injury, EMT	Xuan et al.89
Male C57BL/6 mice	PS: 40 nm	IH/daily	100 μg/day	7 days	ferroptosis, oxidative stress, alveolar-capillary barrier dysfunction, mitochondrial damage	Yang et al.90
C57BL/6 mice	PS: 100, 200 nm	i.t./daily	12.5 25 mg/kg	7 days	pulmonary hemorrhage, oxidative stress, inflammation, collagen deposits, ferroptosis	Wu et al.91
Male C57BL/6 mice	PS: 20 nm	i.n./once per 2 days	5, 10 mg/kg	15 days	oxidative stress, ERs, apoptosis, ferroptosis, lung injury	Wu et al.92
Male C57BL/6 mice	PS: 5.0  μm	drinking water	10 mg/L	/	oxidative stress, inflammation, apoptosis	Tong et al.93
Female C57BL/6 mice	PS: 5.0  μm	i.n./daily	0.5, 1, 2 mg/kg	14 days	pulmonary fibrosis, collagen deposition, ferroptosis, lipid peroxidation	Zhang et al.94
Male C57BL/6 mice	PS: 40 nm	IH/daily	16, 40, 100 μg/day	7, 30, 90 days	oxidative stress, inflammation, COPD, collagen deposition, ERs, mitochondrial dysfunction	Yang et al.67
Male C57BL/6, BALB/c, and ICR mice	PS, PP, PVC	i.t./daily	5 mg/kg	14 days	inflammation, PS > PP > PVC	Danso et al.95
Male/female C57BL/6 mice	tire: 100 nm	IH/daily	0.125, 0.5, 1 mg/kg	28 days	restricted ventilatory dysfunction, fibrosis, collagen deposition, inflammation, destruction of lung barrier	Li et al.96
Male C57BL/6 mice	aged PE: 1, 10, 100 μm	i.p./thrice per week	1.25 mg/kg,	21 days	lung inflammation, 1 μm > 10 μm > 100 μm	Lyu et al.97
Male C57BL/6 mice	PS-amino: 100 nm	i.t/thrice per week	5 mg/kg	7 days	lung index, lung injury, mucin secretion, oxidative stress, inflammation, Irg1, pyroptosis	Wu et al.98
Male C57BL/6 mice	PS: 17.53 ± 2.11 μm, PP: 6.40 ± 1.48 μm, PE: 21.27 ± 6.07 μm	i.t./daily	5 mg/kg	14 days	NLRP3 inflammasome activation, TLRs activation, PS > PP or PE	Kwabena Danso et al.99
Male C57BL/6 mice	PS: 5 μm	i.t./5 times per week	0.6 mg/kg	60 days	lung injury, pulmonary flora disorder, deposition of collagen, lung barrier damage, inflammation	Kang et al.100
Male C57BL/6 mice	PE, PP, PS, PVC: 100–500 nm, from bulk plastic breakdown	IH, daily	1 mg/m3	14 days	lung injury, ferroptosis, autophagy, ferritinophagy, mitochondrial damage, PVC > PS > PET or PVC, NPs from bulk plastic breakdown > raw NPs	Ji et al.101
Male C57BL/6 mice	PS: 5 μm	i.g./thrice per week	0.4 mg/kg	21 days	airway hyper-responsiveness, respiratory resistance, fibrosis	Balkrishna et al.102
Male C57BL/6 mice	PS: 500 nm, 2 μm	i.n./daily	40 mg/kg	21 days	oxidative stress, COPD, ferroptosis, autophagy, mitochondrial dysfunction	Wei et al.79
Male BALB/c mice	PVC: 6.5–25 μm	i.t./daily	25, 50 mg/kg	8 days	lung injury, inflammation, cellular senescence	Jin et al.103
Male BALB/c mice	PS, PS-COOH, PS-NH2: 100 nm	i.g./daily	1 mg/mice	28 days	lung injury, fibrosis, PS-COOH or PS-NH2 > PS	Xu et al.104
Female BALB/c mice	PP (190 μm, 225 nm), PS (180 μm, 52 nm), PET (430 μm, 265 nm)	i.n./once per 2 days	2 mg/kg	48 h	inflammation, lung injury, PS > PET > PP	Xu et al.105
Female BALB/c mice	PA: 3 μm, from nylon cloth	i.n./once per 3 days	250 μg/mice	7 days	asthma, IgE, inflammation, mucus hypersecretion, fibrosis, mucus hypersecretion, apoptosis, disruption of barrier integrity of lung, changes in pulmonary microbiota	Wu et al.106
Female BALB/c mice	PS: 1–5 μm	i.n./once per 3 days	300 μg/mice	24 days	asthma, IgG1, mucus production, inflammation	Lu et al.107
Male BALB/c mice	PS: 42 nm	i.n./once per week	5 mg/kg	28 days	lung injury, fibrosis, inflammation	Tang et al.108
Male ICR mice	PS: 99 nm, 5 μm	i.n./once per 2 days	100 μg/mice	35 days	hemorrhage and exudates, nasal and lung microbial dysbiosis, 5 μm > 99 nm	Zha et al.109
Male ICR mice	PP: 0.66 μm	i.t./5 times per week	1, 2.5, 5 mg/kg	28 days	inflammation, ROS, alveolar epithelial hyperplasia, foamy macrophage aggregates	Woo et al.110
Male ICR mice	PES: 50 nm, 5 μm	i.n./once per 3 days	0.75 mg/kg	42 days	microbial dysbiosis, metabolic disruption, 50 nm > 5 μm	Zha et al.111
Male and female ICR mice	PE: 10–50 μm	i.g./daily	500, 1,000, 2,000 mg/kg	28 days	inflammation	Lee et al.112
Male ICR mice	PS: 20 nm	i.t./daily	5.6, 17, 51 mg/kg	1 day	lung injury, inflammation, unfolded protein response, ERs, protein ubiquitination	Chen et al.113
Male ICR mice	PP, PHA: 5 μm	i.n./once per 3 days	0.75 mg/kg	42 days	oxidative stress, lung injury, microbiome dysbiosis, infiltration, PP > PHA	Zha et al.114
Male ICR mice	PVC, PVA, PHA: 50 nm	i.n./once per 3 days	0.75 mg/kg	42 days	lung injury, microbiome dysbiosis, infiltration, PVC > PVA or PHA	Hua Zha et al.115
Male Mus musculus	PET: 56 nm	i.g./daily	0.5 mg/day	28 days	pulmonary flora disorder	Kaluç et al.116
Male SD rats	PS: 100 nm	IH/daily	0.5, 1.0, 2.0 mg/m3	90 days	pulmonary dysfunction, pulmonary emphysema, extracellular matrix degradation	Sun et al.117
Male SD rats	PS: 100 nm, 500 nm, 1 μm, 2.5 μm	i.t./once per 2 days	0.5, 1, 2 mg/mice	14 days	lung injury, inflammation, change of lncRNA and circRNA	Fan et al.118
Female SD rats	PA: 5  μm	IH	10 mg/m3	4 h	neutrophils, mean arterial pressure, elevated blood pressure, systemic inflammation	Cary et al.119
Male SD rats	PS: 100 nm	i.n./5 times per week	0.5, 1, 2 mg/m3	35 days	lung dysfunction, inflammation, cellular senescence	Luo et al.120
Male/female SD rats	PS: 100 nm	IH/6 h each day, 5 times per week	0.75, 1.50, 3.00 × 105 particles/cm3	14 days	pulmonary dysfunction, inflammation, fibrosis	Lim et al.121
Male/female SD rats	PS: 60 nm	IH/4 h/day, daily	0.5, 1 or 2 mg/m3	90 days	emphysema, cuproptosis, pyroptosis, ubiquitination of protein	Bu et al.122
Broiler chickens	PS: 5 μm	drinking water	1, 10, 100 mg/L	42 days	down-regulation of lung index, oxidative stress, lung injury, autophagy, apoptosis	Lu et al.123
Chickens	PS: 5 μm	drinking water	1, 10, 100 mg/L	42 days	lung injury, ERs, pyroptosis, inflammation	Lu et al.124

i.g., oral gavage; i.n., intranasal; i.t., intratracheal; IH, inhalation; i.p., intraperitoneal; EMT, epithelial-mesenchymal transition.

Pulmonary toxicity varies significantly among different MP and NP types in murine models. Although all MPs cause pulmonary inflammation in mice, PS has demonstrated markedly higher toxicity compared with PP, PET, or PVC.^95,105 Similarly, Kwabena Danso et al.⁹⁹ reported that PS exhibits stronger respiratory toxicity than other common plastic types. Chemical modifications of NPs further intensify respiratory toxicity; for instance, PS-COOH and PS-NH₂ induce more severe pulmonary fibrosis in C57BL/6 mice compared to unmodified PS.¹⁰⁴ Additionally, particle size critically influences lung injury severity, with smaller particles causing greater damage, likely due to deeper tissue penetration and higher surface reactivity.^88,97,128

Recent research on MP toxicity, particularly respiratory impacts in rodent models, has expanded rapidly. However, these studies frequently lack environmental relevance. Investigations exceeding 3 months remain uncommon, neglecting potential chronic effects of inhaled MPs. Similarly, exposure methods seldom mimic real-world conditions, and intranasal and intratracheal administration predominate over inhalation models. Notably, estimated daily human exposure to MPs and NPs is only 8.32 ng/kg,^61,62 whereas laboratory studies typically employ concentrations several orders of magnitude greater. Furthermore, experimental MPs and NPs are usually raw plastic particles, further limiting environmental relevance.

Significant discrepancies also exist across studies regarding pulmonary toxicity, which varies depending on exposure routes. For instance, Zha et al. and Hua et al. reported that MPs and NPs cause greater pulmonary toxicity via inhalation compared to ingestion through food,^114,115 possibly due to reduced lung accumulation following oral exposure. While most studies confirmed that MPs and NPs induce pulmonary inflammation in mice, a single-dose inhalation exposure (9.53 mg/m³ MPs) does not trigger inflammation in SD rats.¹¹⁹ Similarly, exposure of C57BL/6 mice to 10 mg/L PS via drinking water inhibits pulmonary cell autophagy,⁹³ which is inconsistent with other reports.^79,101 Additionally, effects of MPs and NPs on mouse lung index are inconsistent across studies.^87,98,121 These inconsistencies likely arise from differences in exposure methods, particle concentrations, exposure durations, and animal models, as even identical exposures can produce varied inflammatory responses among mouse strains.⁹⁵ Thus, animal model research on MP and NP respiratory toxicity currently lacks standardized methods. Existing methodologies differ extensively regarding MP physicochemical characteristics, exposure routes and dosage, and toxicity endpoints. This methodological variability limits meaningful cross-study comparisons, generating conflicting findings with limited applicability. Consequently, it substantially restricts clear mechanistic insights and reliable human health risk assessments.

Pigs

Cao et al. and Shi et al. investigated the interaction between MPs, NPs, and porcine lung surfactants.^129,130 Their studies revealed that MPs bind to pulmonary surfactants, increasing ROS production and impairing lung function. Notably, aged MPs exhibited greater toxicity, likely due to the formation of environmentally persistent free radicals that exacerbate oxidative stress and cellular damage (Table 2).

Birds

Laboratory studies (Table 2; Figure 3B) provide further evidence of MP-induced pulmonary toxicity in avian models. Chickens exposed to MPs for 6 weeks exhibited oxidative stress in lung tissues.¹²³ MPs also activated autophagy and apoptosis pathways. Moreover, MPs caused significant damage to the microstructure and ultrastructure of chicken lung tissues, including lymphocyte infiltration, inflammatory cell infiltration, tissue necrosis, chromatin condensation, and swelling of plasma membranes and the ER. MPs further induced ERs, pyroptosis, and inflammation in a dose-dependent manner.¹²⁴ Collectively, these findings demonstrate that MPs and NPs can cause substantial and multifaceted pulmonary damage in birds, involving oxidative stress, apoptosis, autophagy, ERs, and inflammatory responses.

Although numerous studies report MP and NP accumulation and toxicity in mammalian lungs, the practical implications and human relevance of these results should be interpreted cautiously. Significant discrepancies exist between experimental designs and real-world exposure scenarios, limiting direct extrapolation to human health. Furthermore, despite rising concerns regarding airborne MP and NP pollution, toxicity assessments primarily focus on human health and laboratory animal models. Consequently, respiratory exposure risks to wildlife have received limited attention. This represents a critical research gap, as wildlife inhabits environments extensively contaminated by MPs and NPs.¹³¹ Addressing this gap is essential to comprehensively evaluate MP- and NP-related risks across ecosystems.

Cellular studies

In vitro, A549 and BEAS-2B cells are commonly used to study respiratory toxicity (details are provided in supplemental information, Table 3, and Figure 3C). MPs and NPs primarily enter these cells via endocytosis, with intracellular particles predominantly localized within lysosomes. The extent of intracellular accumulation depends on exposure duration, particle concentration, and particle size.^{132,142,143,152,159} Exposure to MPs and NPs induces dose-dependent cytotoxicity, including decreased cell viability,^{134,144,147,148} cell-cycle arrest,^143,144 and oxidative stress.^147,150 MPs and NPs also impair mitochondrial function by reducing mitochondrial membrane potential, depleting ATP, and disrupting the tricarboxylic acid cycle.^92,148 In addition, MPs and NPs trigger ERs through activation of the unfolded protein response, as evidenced by upregulated expression of ERs markers such as p-PERK, p-IRE1, p-eIF2α, ATF4, and CHOP.^113,160 Furthermore, MPs and NPs activate multiple programmed cell death pathways, including apoptosis, pyroptosis, and ferroptosis, as well as genotoxicity and barrier integrity disruption.^{92,100,151,152} Recently, advanced in vitro models have been applied to assess the respiratory toxicity of MPs and NPs. MPs inhibit organoid growth and airway epithelial differentiation.¹⁵⁷ Lung-on-a-chip models demonstrated that NPs induce oxidative stress, inflammation, and alveolar-capillary barrier damage.¹⁵⁵ Similarly, MPs and NPs cause oxidative stress and compromise the air-blood barrier in dynamic barrier models.¹⁵⁶

Table 3.

Summary of MPs and NPs in respiratory toxicity studies in vitro

Object	Size	Dose	Time	Toxic effects	Reference
A549 cell	PS: 25, 70 nm	1.14 μg/mL	1, 2, 4, 8, 12 h	cell viability↓, apoptosis, cell cycle S phase arrest	Xu et al.132
A549 cell	PP: 0.66 μm	1, 2, 4 mg/mL	16 h	cell viability↓, mitochondrial dysfunction, oxidative stress, inflammation	Woo et al.110
A549 cell	PTFE: 6.0, 31.7 μm	10, 100, 500, 1000 μg/mL	24, 48 h	NO, oxidative stress, apoptosis, inflammation	Maharjan et al.133
A549 cell	PS, 85.98 nm	3.125, 6.25, 12.5, 25, 50, 100 μg/mL	24, 48 h	cell viability↓, apoptosis, facilitation of influenza A virus infection	Wang et al.134
A549 cell	PS: 1–5 μm, 10–20 μm	0, 100, 250, 500 μg/mL	48 h	apoptosis, inflammation, oxidative stress, 1–5 μm > 10–20 μm	Cao et al.88
A549 cell	PS: 1, 10 μm	5 μg/mL	60, 72, 96 h	changes in cell morphology, cell viability↓	Goodman et al.135
A549 cell	PE, PP: 5–15 μm, from plastic waste	0.1, 1, 10, 100 μg/mL	24 h	cell viability↓, DNA damage, inflammation	Bengalli et al.136
A549 cell	PS, PS-amino: 20 nm, 50 nm	10, 20, 40 μg/mL	24 h	cell viability↓, oxidative stress, EMT, mitochondrial dysfunction, ERs, PS-amino > PS, 20 nm > 50 nm	Halimu et al.137
A549 cell	PS, PS-NH2, PS-COOH: 80 nm, 2 μm	50, 100, 200, 400 μg/mL	24 h	cell viability↓, oxidative stress, DNA damage, PS-NH2 or PS-COOH > PS, 80 nm > 2 μm	Shi et al.138
A549 cell	PET: 167.0 nm, from food containers	1.95, 15.6, 125 μg/mL	3, 24 h	cell viability↓, oxidative stress, DNA strand breaks	Alzaben et al.139
A549 cell	aged PF, 12.13–14.61 μm	1,000 μg/mL	14, 28 d	cell viability↓, oxidative stress, LDH	Zhu et al.140
A549 cell	PS-COOH, PS-NH2, PS: 1 μm	10 μg/mL	3-24 h	lipid coronas led to significantly enhanced uptake of particles	Dorsch et al.141
A549 cell	PET: 122–221 nm	4.92, 49.2 μg/mL	24 h	cell viability↓, oxidative stress, mitochondrial dysfunction, cell apoptosis rate↓	Zhang et al.142
A549 cell	PS: 800 nm	10, 100, 500 μg/mL	24, 48, 96 h	cell viability↓, oxidative stress, cellular senescence, apoptosis	Milillo et al.143
A549 cell	PS, aged-PS: 1, 5  μm	1, 10 μg/mL	24 h	metabolic disorder, cytoskeleton destruction, cell cycle G2 arrest, accumulation, morphological changes, 1  μm > 5  μm, aged PS > PS	El Hayek et al.144
A549 cell	PS, PS-NH2: 50 nm, 200 nm, 1 μm	1, 10, 100 μg/mL	24, 72 h	cell viability↓, oxidative stress, cell cycle G2 arrest, apoptosis, inflammation response, PS-NH2>PS	da Silva Brito et al.145
A549 cell	PS: 54.46 nm, PET: 781.0 nm	1, 10, 100 μg/mL	24 h	cell viability↓, oxidative stress, inflammation, autophagy, DNA damage, metabolic disorder	da Silva Brito et al.146
A549 cell	PS: 60 nm	62.5, 125, or 250 μg/mL	24 h	pyroptosis	Bu et al.122
A549 cell	PS: 5  μm	25, 50, 100 μg/mL	24 h	cell viability↓, lipid peroxidation, ferroptosis	Zhang et al.94
BEAS-2B cell	PS: 1.72 μm	10, 1,000  μg/cm2	24, 48 h	cell viability↓, oxidative stress, cell shrinkage, inflammation, pulmonary dysfunction	Dong et al.147
BEAS-2B cell	PS: 80 nm	6, 12.5, 31.25, 62.5, 125, 250 mg/mL	1, 48 h	cell viability↓, mitochondrial damage, mitochondrial metabolic disorders	Lin et al.148
BEAS-2B cell	PVC: 1,232 nm	100, 200, 400, 600, 800 μg/mL	24 h	cell viability↓, metabolic disorders	Liu et al.149
BEAS-2B cell	PS, PS-NH2, PS-COOH: 100 nm	12.5, 25, 50, 100, 200 μg/mL	3, 6, 24 h	cell viability↓, oxidative stress, ERs, autophagy, PS-NH2 > PS-COOH > PS	Jeon et al.150
BEAS-2B cell	PS: 40 nm	7.5, 15, 30 μg/cm2	24 h	cell viability↓, autophagy, oxidative stress, ferroptosis	Yang et al.90
BEAS-2B cell	PS: 100, 200 nm	100, 200, 400 μg/mL	24 h	oxidative stress, ferroptosis	Wu et al.91
BEAS-2B cell	PS: 20 nm, 10 μm	0.2 mg/mL	24 h	cell viability↓, oxidative stress, mitochondrial damage, apoptosis, ERs, ferroptosis, NPs > MPs	Wu et al.92
BEAS-2B cell	PE: 6.5–1,000 μm, PP:6.5–100 μm, PS: 3–100 μm, PVC: 6.5–25 μm	0.5, 5 μg/mL	24 h	cell viability↓, oxidative stress, cellular senescence, inflammation PE > PP or PS or PVC	Jin et al.103
BEAS-2B cell	tire: 100 nm	25, 50, 100 μg/mL	24 h	cytoskeleton rearrangement, cell migration	Li et al.96
BEAS-2B cell	PS: 40 nm	7.5, 15, 30 μg/mL	24 h	cell viability↓, oxidative stress, inflammation, apoptosis, alveolar epithelial barrier damage, pulmonary dysfunction	Yang et al.151
BEAS-2B cell	PS: 20 nm	0, 7.5, 15, 30 μg/mL	24 h	ERs, protein ubiquitination, unfolded protein response	Chen et al.113
BEAS-2B cell	PS: 153 nm	1, 10, 100, 1,000 ng/cm2,	24 h	cell viability↓, oxidative stress, inflammation, apoptosis, autophagy, lung barrier injury	Chen et al.152
BEAS-2B cell	PS: 5 μm	1, 5, 10, 20 μg/mL	24 h	cell viability↓, oxidative stress, ferroptosis	Kang et al.100
BEAS-2B cell	PE, Aged-PE: 147, 582, 12,500 nm	0.032,0.32,3.2 mg/mL	24 h, 48 h	cell viability↓, oxidative stress, epithelial-mesenchymal transition, inflammation, mitochondrial metabolic disorders, morphological change, autophagy	Vailionytė et al.153
BEAS-2B cell	PS: 42 nm	60, 120, 250, 500, 1,000 μg/mL	24 h	cell viability↓, oxidative stress, inflammation, apoptosis	Tang et al.108
HBE cell	PS: 50–100 nm	–	24 h	epithelial-mesenchymal transition	Xuan et al.89
Calu-3 cell	PLA: 130.06 nm	2.5, 10, 20 μg/cm2	24 h, 7 days, 14 d	oxidative stress, tight junction damage, destruction of barrier, DNA damage	García-Rodríguez et al.154
TC-1 cell	PE, PP, PS, PVC: 100 nm–500 nm, from bulk plastic breakdown	100 μg/mL	24 h	cell viability↓, ferroptosis, autophagy, ferritinophagy, mitochondrial damage, PVC > PS or PET or PVC	Ji et al.101
THP-1 cell	PS: 100 nm	200, 400, 600 μg/mL	48 h	cell viability↓, extracellular matrix degradation	Sun et al.117
MLE12 cell	PS: 100 nm	100, 200, 400 μg/mL	48 h	cell viability↓, cellular senescence	Luo et al.120
MLE12 cell	PS: 100 nm	12.5 μg/mL	12 h	pyroptosis, activation of murine alveolar macrophages	Wu et al.98
Lung-on-a-chip	PS: 60 nm	7.5, 15, 30 μg/mL	24 h	alveolar-capillary barrier damage, oxidative stress, cell death, inflammation	Yang et al.155
Dynamic air-blood barrier model	PET: 0.20, 1.68, 16.5 μm	10, 100, 1000 μg/cm2	24 h	air-blood barrier damage, oxidative stress	Fu et al.156
Airway-type organoids	PET, nylon: 1–10 μm, from fabrics	1, 10, 100 μg/mL	14 days	inhibition of growth of organoids, inhibition of differentiation of airway epithelium	Song et al.157
3D lung organoid model	PS, 240, 1,000 nm	1, 10 μg/cm2	14 days	barrier damage	Ernhofer et al.158
Pulmonary surfactant	PP (190 μm, 225 nm), PS (180 μm, 52 nm), PET (430 μm, 265 nm): from lunch box, foam box, and water bottle	10, 100, 1,000 μg/mL	24 h	inhibition of biophysical function of the pulmonary surfactant, PS > PET > PP	Xu et al.105

PTFE, polytetrafluoroethylene; ↓, downregulation.

Particle size and surface modifications of MPs and NPs significantly influence cytotoxicity in lung cell models. Generally, smaller particles exhibit greater toxicity, likely due to increased cellular uptake.¹³² For instance, NPs are more toxic than MPs. Nano-sized NPs induce greater cytotoxicity and genotoxicity in A549 cells compared with their micro-sized counterparts.¹³⁸ Halimu et al.¹³⁷ reported significantly lower cell viability in A549 cells exposed to 20 nm PS NPs compared with those exposed to 50 nm PS NPs. Similarly, Wu et al.⁹² demonstrated that PS NPs (20 nm) cause damage in BEAS-2B cells, whereas PS MPs (10 μm) do not exhibit toxicity under the same exposure conditions. Beyond particle size, physicochemical modifications further enhance MP and NP toxicity. Oxidized particles intensify oxidative stress, mitochondrial dysfunction, and DNA damage in A549 cells,¹⁶¹ while chemical surface modification with amino groups further reduces cell viability and promotes apoptosis.^138,145 Other modifications, such as photoaging and surface charging, have also been demonstrated to increase cytotoxicity in A549 cells.^137,140,144 Furthermore, co-exposure to MPs and NPs or plastic additives may amplify their adverse effects. For example, combined exposure to MPs and plastic additives enhances oxidative stress in A549 cells.¹⁶² Similarly, simultaneous exposure to different MPs and NPs further decreases cell viability, increases oxidative and inflammatory responses, and exacerbates mitochondrial dysfunction.^139,163,164

Polymer type also influences toxicity levels. Among tested plastics, PVC induces slightly higher levels of ferroptosis and autophagy compared with other common polymers in TC-1 cells.¹⁰¹ In contrast, PE causes more pronounced oxidative stress and inflammation in BEAS-2B cells.¹⁰³ Discrepancies occasionally emerge between in vitro and in vivo studies. For example, PS induces more severe pulmonary toxicity in vivo,^95,105 whereas in vitro studies indicated that PE or PVC causes greater cellular damage.^101,103 The mechanisms underlying these differences require further investigation.

Although in vitro studies provide important insights into the respiratory toxicity of MPs and NPs, their environmental relevance remains limited. Many experiments use acute exposure regimens and concentrations considerably higher than environmental levels, neglecting chronic, low-dose exposure representative of real-world scenarios. Additionally, widespread use of pristine, commercially available MPs fails to capture the chemical and physical complexity of environmental MPs. Another limitation is reliance on conventional two-dimensional monoculture systems, which poorly mimic the structural and functional complexity of human respiratory tissues. While cell-based models offer methodological convenience, their inability to replicate tissue-level responses highlights the need for physiologically relevant systems, such as respiratory organoids, to better align mechanistic toxicology studies with realistic environmental exposure.

The “Trojan horse” effect: Joint study of MPs and NPs with other pollutants

MPs and NPs, due to their high surface energy, exhibit a strong capacity to adsorb various environmental pollutants, forming complex composites.^165,166 Conversely, MPs and NPs themselves can also be adsorbed by airborne pollutants, such as particulate matter (PM₁₀).⁸¹ These pollutant-plastic composites can deposit in the alveoli and elicit combined respiratory toxicity.^125,167 Epidemiological studies have shown that MP-heavy metal complexes are associated with an increased risk of lung adenocarcinoma.⁵⁹ Laboratory findings support this, demonstrating that co-exposure to NPs and cigarette smoke condensate enhances oxidative stress, genotoxicity, and tumorigenic transformation in BEAS-2B lung epithelial cells.¹⁶⁸ Similarly, MPs have been shown to exacerbate lung and cell injury caused by heavy metals.^93,169,170 In vitro studies reveal that NPs intensify the cytotoxic effects of ozone, Platanus pollen allergenic protein 3, polycyclic aromatic hydrocarbons, and phthalates on A549 cells.^{163,171,172,173} In addition, compounds such as lactate and dibutyl phthalate (DBP) can aggravate MP- and NP-induced lung injury via the gut-lung axis.^89,174,175 MPs also exacerbate DBP-induced allergic asthma,¹⁷⁶ and co-exposure to MPs and house dust mites promotes airway inflammation and disrupts epithelial barrier integrity in mice.¹⁷⁷ Moreover, MPs worsen ovalbumin (OVA)-induced asthma through alterations in the pulmonary microbiota.¹⁰⁶ Notably, 1 μm MPs have been found to intensify the inflammatory response in mice with mild COVID-19.¹⁷⁸ While the combined effects of MPs and NPs with other pollutants are established, further analysis of the bioavailability of other pollutants carried by MPs and NPs is needed. Current research on combined effects primarily focuses on in vitro experiments, making it difficult to analyze the mechanisms by which MPs and NPs act as carriers.

How: Potential mechanisms for respiratory toxicity of MPs and NPs

Respiratory studies related to MPs and NPs were retrieved from the Web of Science Core Collection, with the detailed search strategy outlined in Figure S1. As shown in Figure 4A, aside from the core terms “MPs” and “NPs,” the most frequent keywords were “oxidative stress” (n = 35) and “inflammation” (n = 23). Other prominent keywords included “apoptosis,” “autophagy,” “ferroptosis,” “NLRP3 inflammasome,” “genotoxicity,” “fibrosis,” and “asthma.” Notably, the strong association of these keywords with oxidative stress and inflammation suggests that these processes act as central mediators of respiratory toxicity induced by MPs and NPs. Based on this observation, we further summarized and analyzed the key molecular pathways and targets involved in MP- and NP-induced respiratory toxicity (Figure 4B).

Figure 4.

Potential pathogenic mechanisms of MPs and NPs in the respiratory system

(A) Network visualization analysis of co-occurring keywords in studies on the respiratory toxicity of MPs and NPs. Node size reflects keyword frequency.

(B) Schematic illustrating the respiratory toxicity of MPs and NPs.

Cellular uptake of MPs and NPs

MPs and NPs can access the lungs through inhalation or systemic circulation via the bloodstream. At the cellular level, MPs and NPs are primarily internalized through endocytosis rather than receptor-mediated uptake.^136,152,179 Consequently, the number of particles internalized by lung cells strongly depends on exposure concentration. Recent research identified integrin α5β1-mediated endocytosis as a critical pathway promoting NP uptake by lung cells,¹⁸⁰ indicating that MP and NP uptake may also be regulated by specific molecular pathways. Additionally, particle size significantly influences uptake. Smaller MPs and NPs are more readily internalized, whereas larger particles are less easily eliminated by exocytosis.^{87,132,159,181} The physicochemical properties of MPs and NPs further impact cellular uptake. Aged or positively charged MPs and NPs accumulate more readily in lung tissues.^182,183 Additionally, components of the lung microenvironment, including mucins and pulmonary surfactants, affect the endocytic process.^66,125 Specifically, mucins enhance microparticle uptake via micropinocytosis and delay their excretion from cells. In summary, MPs and NPs primarily enter lung cells through endocytosis, a process influenced by exposure concentration, particle size, surface charge, chemical modifications, and interactions with lung-secreted biomolecules.

Oxidative stress

MPs and NPs increase ROS and MDA levels in lung tissues and pulmonary cell lines. Nuclear factor erythroid 2-related factor 2 (Nrf2) expression is downregulated in A549 cells following exposure to NPs.¹⁴⁶ Furthermore, MP and NP exposure decreases antioxidant enzyme activities, such as total antioxidant capacity, SOD, GSH, and CAT, in in vivo and in vitro models.^{67,90,151,184} Mitochondria, as the primary sites of ROS generation, are also key targets of environmental pollutants. MPs and NPs induce mitochondrial damage, including swelling, loss of cristae, and reduced membrane potential,^{92,101,110,148} along with elevated mitochondrial reactive oxygen species production.^79,101,148 These findings suggest that MPs and NPs may directly target mitochondria, exacerbating oxidative stress in the respiratory system. Several studies have demonstrated that inhibiting oxidative stress alleviates respiratory effects induced by MPs and NPs.^{90,98,103,185} Thus, MPs and NPs induce oxidative stress by suppressing antioxidant defenses and enhancing ROS production, recognized as critical initiating factors in respiratory toxicity. However, the precise reasons behind excessive ROS generation from MP and NP exposure remain unclear. Some studies reported enhanced antioxidant enzyme activity following MP and NP exposure,^93,143 contradicting findings of reduced antioxidant activity and elevated ROS levels. Moreover, environmentally persistent free radicals on MP surfaces, particularly on aged MPs, significantly contribute to ROS generation in lung cells.¹²⁹ A nuanced understanding of oxidative stress initiation is essential to clarify mechanisms underlying respiratory toxicity induced by MPs and NPs.

Inflammation

MPs and NPs have attracted increasing attention due to their role in pulmonary inflammation, a major toxicological outcome.¹⁸⁶ Both in vivo and in vitro studies have demonstrated that MPs and NPs promote inflammatory cell infiltration and elevate the expression of key pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β.¹⁸⁷ Nuclear factor κB (NF-κB) is a central transcription factor regulating inflammatory responses.¹⁸⁸ Recent studies have demonstrated that MPs and NPs activate the NF-κB pathway through phosphorylation, promoting pulmonary inflammation.^{88,110,176,189,190} Mechanistic investigations suggest that this activation is mediated through mitochondrial damage and Toll-like receptor (TLR) signaling.^88,99,110 Oxidative stress is also recognized as a key upstream regulator of NF-κB activation following MP and NP exposure.^98,175,176 Additionally, the NLRP3 inflammasome plays a critical role in MP- and NP-induced lung inflammation. Elevated IL-1β levels may result from NLRP3-mediated cleavage of gasdermin D (GSDMD), leading to inflammatory pyroptosis.^124,190 MPs and NPs can also indirectly promote pulmonary inflammation by inducing microbiota imbalances and metabolic disturbances.^{111,116,127,191} Notably, such chronic inflammatory responses have been linked to the development and exacerbation of respiratory conditions, such as asthma and COPD.^{106,128,176,192} Thus, MPs and NPs induce pulmonary inflammation primarily via mechanisms involving the NF-κB pathway.

Cell death

Apoptosis

Recent studies indicate that exposure to MPs and NPs significantly increases the number of apoptotic cells both in vivo and in vitro.^{88,92,106,132,134,144,145} MPs and NPs reduce mitochondrial membrane potential (ΔΨm) in lung cells,¹⁴² likely due to oxidative stress or an elevated Bax/Bcl-2 ratio. This dysfunction facilitates Cyt-c release into the cytosol, subsequently activating caspase-9 and triggering caspase-3 cleavage. Collectively, these findings indicate that MPs and NPs induce mitochondrial damage, reduce ΔΨm, and activate the intrinsic apoptotic pathway through the Cyt-c/caspase-9/caspase-3 axis in lung cells. Emerging research also suggests that ERs contributes to NP-induced lung cell apoptosis.⁹² Notably, the transcription factor CHOP, a key mediator of ERs-induced apoptosis, is significantly upregulated following NP exposure, along with elevated expression of ERs markers, including phosphorylated IRE1α, p-PERK, activating transcription factor 6 (ATF6), and spliced XBP1 (XBP1s).^113,150,193 A critical knowledge gap remains regarding whether ERs-initiated signals dominate apoptotic cascades or amplify mitochondrion-mediated pathways. Importantly, oxidative stress may serve as an upstream trigger for ERs activation in this context.⁹² MPs and NPs may also induce apoptosis through cell cycle disruption, evidenced by altered cell cycle progression in lung cells exposed to MPs and NPs.^{120,132,144,194}

Pyroptosis

Pyroptosis is a pro-inflammatory form of programmed cell death primarily mediated by the NLRP3/caspase-1/GSDMD signaling pathway. Exposure to MPs and NPs activates the NLRP3 inflammasome in lung tissues, as evidenced by cleavage of both caspase-1 and GSDMD, confirming the induction of pyroptosis in lung cells.^{88,95,98,99,106,195} Further studies indicated that oxidative stress-mediated ERs and NF-κB signaling pathways also contribute to MP- and NP-induced pyroptosis.^98,124 Thus, MPs and NPs initiate pyroptosis through the NLRP3/caspase-1/GSDMD axis, modulated by upstream oxidative stress, ERs, and NF-κB activation. Notably, pyroptosis has been implicated in the emphysematous changes induced by MPs and NPs in lung tissues.¹²²

Ferroptosis

Ferroptosis is a regulated form of cell death characterized by intracellular ferrous iron (Fe²⁺) accumulation, promoting membrane lipid peroxidation via the Fenton reaction. Exposure to MPs and NPs results in increased levels of MDA and intracellular Fe²⁺ alongside reduced GSH and GPX4 levels in mouse lung tissues.^94,100 These findings suggest that MPs and NPs induce ferroptosis in the lungs. Mitochondrial and ER dysfunction significantly contribute to MP- and NP-induced ferroptosis. On the one hand, oxidative stress-induced mitochondrial damage facilitates ferroptosis in lung tissue.^67,79,90,101 On the other hand, ERs has also been implicated in ferroptosis following MP and NP exposure.⁹² Recent studies have further identified the involvement of the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) and microbiota/TLR4 signaling pathways in MP- and NP-induced ferroptosis.^94,100 Notably, ferroptosis is recognized as a key pathological mechanism underlying COPD and pulmonary fibrosis induced by MPs and NPs.^67,79,100 In summary, MPs and NPs trigger ferroptosis in lung cells through intracellular iron accumulation, GPX4 suppression, oxidative stress, mitochondrial injury, and ERs mechanisms.

Autophagy

Exposure to MPs and NPs triggers autophagy in lung cells and primary human nasal epithelial cells, indicated by increased phosphorylation of mammalian target of rapamycin (mTOR), elevated formation of the autophagy-related proteins LC3 and ATG5, and degradation of p62.^{79,123,146,196} Additionally, MP exposure is associated with lysosomal accumulation in BEAS-2B cells,¹⁵⁰ suggesting lysosomal involvement in autophagy. MPs also induce mitophagy, a selective autophagic process targeting damaged mitochondria. MPs upregulated Parkin expression, a hallmark mitophagy protein, along with increased LC3, Beclin1, and ATG7 levels, promoting mitochondrial autophagy in lung cells.¹⁹⁷ Notably, oxidative stress and the associated mitochondrial damage appear to be critical as upstream triggers for MP- and NP-induced autophagy and mitophagy.^79,90,197 The role of autophagy in MPs respiratory toxicity is complex. Initially, autophagy may protect cells by clearing damaged organelles; however, extensive damage can directly induce cell death or amplify toxicity via other cell death pathways. Current research remains largely descriptive, and the functional role of autophagy is not fully understood, hindering comprehensive insights into MP-induced toxic mechanisms.

In summary, current evidence supports that MPs and NPs trigger apoptosis, pyroptosis, ferroptosis, and autophagy through distinct molecular pathways. However, studies of these cell death mechanisms remain fragmented, and the complex interactions among these pathways are still poorly characterized. Future research should utilize specialized tools, such as gene knockout mouse models, to clarify interactions among different cell death processes.

DNA damage

Accumulating evidence indicates that exposure to NPs induces DNA strand breaks in human lung cells. Elevated DNA damage levels, including formation of micronuclei and increased expression of γ-H2AX, APEX1, ATM, RAD51, MSH2, and XRCC1, have been observed following MP and NP exposure.^{139,154,180,187} Critically, several studies have shown that oxidative stress is closely associated with MP- and NP-induced DNA damage in lung cells.^139,154,187 Notably, MPs exhibit the highest detection rate in lung cancer tissue,¹⁹⁸ suggesting a potential link between MP exposure and lung carcinogenesis.^28,158,199 This association likely arises from persistent DNA damage and genomic instability induced by MPs and NPs. Furthermore, NPs promote epithelial-mesenchymal transition (EMT) in human bronchial and alveolar epithelial cells and A549 cells.^137,200,201 EMT enhances cellular invasiveness and metastatic potential, accompanied by upregulated lung cancer-related genes.²⁰² Collectively, these findings suggest that MPs and NPs potentially contribute to carcinogenesis via DNA damage. However, current studies primarily rely on short-term, high-dose in vitro models. The link between MP and NP exposure and lung tumors still requires extensive animal experiments and high-quality epidemiological evidence.

Lung barrier damage and fibrosis

MPs and NPs compromise the lung barrier by reducing the expression of proteins associated with both tight and adherent junctions.^{100,106,147,151,154,156,184} They may also impair pulmonary barrier function by disrupting surfactant composition and activity, which are essential for maintaining alveolar stability and gas exchange.^{66,105,154,170,203} Additionally, pulmonary fibrosis, a severe consequence of inhaling MPs and NPs, has attracted increasing attention.^24,94,96,204 MP exposure significantly increases collagen deposition and expression of fibrosis markers, including alpha-smooth muscle actin and type I collagen (collagen I).^88,94,205 Mechanistic studies indicated that MP-induced pulmonary fibrosis is primarily mediated by oxidative stress-triggered activation of the Wnt/β-catenin signaling pathway.²⁰⁵ Ferroptosis, cytoskeletal rearrangement, and the NF-κB signaling pathway also contribute to MP- and NP-induced fibrosis.^94,96,200 Moreover, MPs can promote EMT, a key fibrosis process triggered by dysfunction of mitochondria and ER.¹³⁷ Importantly, lung barrier damage and fibrosis represent key mechanisms underlying COPD and asthma development following MP and NP exposure.^106,155

In summary, the mechanism analysis revealed that MPs and NPs are internalized by lung cells primarily through endocytosis. Oxidative stress and inflammation are identified as key initiating factor in MP- and NP-induced pulmonary toxicity, leading to various forms of programmed cell death, pulmonary fibrosis, asthma, and COPD. In the future, oxidative stress and inflammation may serve as critical targets for mitigating the pulmonary toxicity of MPs and NPs.

Limitations and future prospects

Advancement and standardization of detection

Detecting MPs and NPs is the initial step toward evaluating respiratory toxicity. However, comprehensive detection methods with sufficient specificity and sensitivity regarding particle size, shape, and mass concentrations remain limited. Currently, FTIR, Raman spectroscopy, and Py-GC/MS remain the primary methods used to identify plastic particles in the air and lung tissues (Tables 1 and S1). Existing approaches mostly detect particles at micrometer scale, potentially overlooking smaller particles and leading to underestimation of total exposure. Environmental plastic particles differ considerably in source, size, shape, and chemical composition, complicating accurate evaluation of their respiratory effects using current technologies. Another significant challenge is the substantial variability in reported MP concentrations across studies (Tables 1 and S1), primarily due to the absence of standardized sampling and analytical procedures. The widespread presence of MPs and NPs further contributes to uncertainty, especially due to plastic-based consumables commonly used during sampling and testing.

Current limitations of MP and NP detection significantly restrict respiratory toxicity research. Future studies should prioritize improving detection accuracy and quantification by (1) developing and implementing innovative, high-resolution, high-throughput, and cost-effective detection methods, particularly quantitative imaging techniques for NPs, and creating integrated platforms combining multiple detection principles; (2) establishing standardized operating procedures, including reference standards for different plastic types and sizes, covering sampling, processing, analysis, and reporting; and (3) shifting from qualitative and basic quantitative analyses toward intelligent prediction, using machine learning to integrate physicochemical properties of MPs and NPs into advanced respiratory exposure risk assessment models (Figure 5A).

Figure 5.

Research gaps and future prospects regarding the respiratory toxicity of MPs and NPs

(A) Detection, (B) Epidemiology, (C) Experiment, (D) Policies.

Epidemiological investigation

The global incidence of chronic respiratory diseases is rising steadily and remains one of the leading causes of mortality worldwide.²⁰⁶ Among the contributing factors, environmental pollutants have emerged as major threats to respiratory health.¹⁹ A major limitation of current studies is reliance on animal experimental models, which may not fully represent the complexity of human exposure. Although a limited number of studies confirm the presence of MPs and NPs in human lung tissues, evidence suggests that these particles potentially contribute to respiratory diseases such as pneumonia and emphysema.^23,73,74,75 However, research on respiratory toxicity from MPs and NPs in human populations is still a “young” field. Most investigations are cross-sectional with small sample sizes (Table 1), unable to establish causality or accurately assess respiratory impacts. Infants and children are particularly vulnerable to MPs and NPs due to an immature respiratory system and higher ventilation rate per body weight compared to adults.²⁰⁷ Individuals with chronic respiratory disease also exhibit greater sensitivity to environmental pollutants. Therefore, future studies should (Figure 5B) (1) conduct large-scale, multicenter, longitudinal cohort research to monitor respiratory health across populations with varying exposure levels, clarifying epidemiological relationships between MP/NP exposure and respiratory disease, identifying specific biomarkers for population exposure assessment and early health effects warning; (2) focus on sensitive groups, including occupationally exposed individuals (e.g., textile workers, plastic industry employees, and traffic police) and vulnerable populations (children, the elderly, and chronic respiratory patients); and (3) evaluate respiratory effects of MPs and NPs on wildlife, addressing current research gaps.

Laboratory research: From environment to practice

Dose-effect relationship

The toxic effects of a substance depend strongly on exposure dose. The extent and nature of toxicity are largely determined by exposure quantity.^208,209 Even substances regarded as non-toxic or minimally toxic can cause harm if exposure exceeds a certain threshold. In vitro studies investigating pulmonary toxicity of MPs typically select dosages based on cell viability assays, such as the CCK-8 test. However, concentrations used frequently surpass actual environmental levels detected in human body fluids. Similarly, in vivo studies rarely reflect realistic environmental exposure to MPs and NPs. Physiological and metabolic differences between humans and model organisms, such as mice, further complicate extrapolation of experimental findings. Evidence suggests that humans might be more susceptible to environmental pollutants than other mammals,²⁰⁹ partially justifying the use of higher doses in experiments to simulate potential human outcomes. Tomonaga et al. concluded that respiratory toxicity risks in humans are likely low at typical environmental concentrations of MPs.¹⁸⁶ They further suggested chronic lung diseases associated with variations in MP surface functional groups may not pose significant health risks.²¹⁰ Similarly, Meindl et al. observed that healthy cells could adapt to low concentrations of MPs and NPs without substantial damage.²¹¹ Xiao et al. also reported no detectable lung injury in mice exposed to 10 mg/kg NPs over 30 days²¹² Current research predominantly examines short-term respiratory effects, providing limited evidence regarding chronic outcomes from prolonged exposure. Future animal and cellular studies should emphasize low-dose, long-term exposure to identify toxic effects at realistic environmental concentrations, especially clarifying dose-response relationships (Figure 5C).

Diverse MPs and NPs

Plastics contain various chemical additives, including endocrine disruptors, plasticizers (e.g., phthalates), flame retardants, bisphenol A, and other compounds.^213,214 MPs and NPs can act as vectors, transporting these chemicals into the human body. In vivo and in vitro pulmonary toxicity studies report differing toxicity levels among plastic types, likely reflecting variations in chemical composition and released substances.¹⁵⁵ This raises a critical question: are health hazards from MPs and NPs due to the particles themselves, their leached chemicals, or both?^{139,215,216,217} Environmental MPs and NPs encountered by humans vary greatly in polymer type, size, shape, and surface properties. However, most respiratory toxicity studies use pristine MPs as standardized reference materials, thus overlooking chemical diversity and complexity in real-world degraded plastics. Future studies should prioritize assessing respiratory toxicity of environmentally relevant MPs and NPs, especially aged or weathered plastics, to clarify distinctions from other environmental particles and identify mechanisms underlying their respiratory entry.

The “Trojan horse” effect: 1 + 1 = ?

Due to their high surface energy, MPs and NPs readily to adsorb various environmental pollutants, forming complex composites.¹⁶⁵ Epidemiological studies have shown that MP-heavy metal complexes correlate with increased risk of lung adenocarcinoma.⁵⁹ Laboratory studies support these findings.^{93,106,168,169,170,172} However, at low concentrations, NPs may reduce phthalate-induced cytotoxicity by adsorbing phthalates and decreasing their bioavailability.¹⁶³ It remains unclear whether MPs and NPs carrying adsorbed pollutants exhibit greater bioavailability and toxicity compared to pollutants alone. To address this issue, future studies should (Figure 5C) (1) investigate mechanisms influencing pollutant bioavailability when transported by MPs and NPs, (2) examine the pulmonary toxicity of MPs or NPs combined with environmental pollutants, and (3) apply robust statistical models to classify and quantify combined effects, such as additive, synergistic, or antagonistic interactions.

New models and mechanisms

Laboratory studies employing realistic exposure conditions aim to move beyond description toward understanding underlying mechanisms. Although current studies identify various respiratory toxicity mechanisms induced by MPs and NPs, the data generally lack depth and coherence. Therefore, multi-omics techniques and novel experimental models are required (Figure 5C). Multi-omics approaches offer comprehensive strategies for toxicological research. Emerging evidence suggests that MPs cause lung injury by disrupting microbiota composition and host metabolism.¹¹⁴ Integrated metabolomics and RNA sequencing analyses revealed that MPs trigger apoptosis in BEAS-2B lung epithelial cells by disrupting lipid metabolism.^149,218 Furthermore, metabolomics and lipidomic profiling confirmed that MPs exacerbate pulmonary injury in diabetic mice through metabolic dysregulation.²¹⁹ Future MP and NP studies should integrate multi-omics with computational toxicology to elucidate complex biological responses, clarify toxicity mechanisms, and facilitate risk assessment and precision toxicology. Traditional animal models simulate human biology and diseases but have limitations due to interspecies differences and ethical concerns. Recent advances in organoid technology offer a promising alternative, as organoids accurately replicate human organ structure and function in response to external stimuli, including MPs and NPs. Thus, organoids may overcome some limitations inherent in traditional animal models.^220,221 For example, Song et al. demonstrated that MPs inhibit the formation of alveolar epithelial-like organoids.¹⁵⁷ Despite their potential, studies exploring respiratory effects of MPs and NPs using organoid models remain limited. Future research should prioritize lung organoids and advanced in vitro models to better characterize MP- and NP-induced respiratory injury mechanisms and bridge gaps between cellular and in vivo studies.^222,223

Future investigations must explore novel mechanisms. Recent studies showed that maternal MP exposure during pregnancy induces oxidative stress, metabolic disturbances, and transcriptional dysregulation in offspring mouse lungs.^185,224 Emerging evidence also suggests that non-coding RNAs contribute to MP- and NP-induced pulmonary diseases, including emphysema and pulmonary fibrosis.^{96,117,120,225} However, investigations of other epigenetic mechanisms, such as histone modifications and DNA methylation, remain limited regarding MP- and NP-induced respiratory toxicity. Recent studies further indicate that MPs and NPs may indirectly induce lung injury via other organ systems, particularly the digestive and cardiovascular systems.¹²⁶ For example, NPs induce pulmonary fibrosis in mice by reducing indole-3-lactic acid levels,²²⁶ while DBP exacerbates MP- and NP-induced lung injury via the gut-lung axis.^174,175 These findings underscore the importance of systemic perspective when evaluating the respiratory toxicity of MPs and NPs. Future research should clarify the roles of diverse epigenetic modifications and multisystem interactions in MP- and NP-induced pulmonary effects and explore how these new mechanisms interactively influence gene regulation, lung development, and long-term respiratory health.

Public health policies

Airborne particulate matter represents a major risk factor for respiratory diseases. Given the widespread presence of MPs and NPs, human exposure occurs daily. Most current studies of MP and NP respiratory toxicity remain isolated, limiting comparability and a comprehensive understanding of their contribution to respiratory disease burdens. Standardized exposure concentrations, particle size classifications, and plastic types could reduce inconsistencies. Additionally, collaboration among researchers and institutions is essential for developing unified standards.

Although uncertainties remain regarding respiratory health risks from MPs and NPs, plastics have undeniably permeated nearly all ecosystems,^3,6,7,8,10 including lung tissues (Table 1). Plastic production is projected to double by 2050, posing severe threats to both the environment and public health.⁵ This scenario urgently requires mitigation strategies and public health policies. The World Health Organization, European Union, and United Nations Environment Program have initiated efforts to address MP- and NP-related health risks, but policy implementation remains challenging and demands international coordination and cooperation.^{227,228,229,230} Key measures include (Figure 5D) (1) addressing knowledge gaps in MP quantification, exposure assessment, and respiratory toxicity to support plastics treaty implementation; (2) reducing plastic production and promoting biodegradable alternatives with minimal environmental and respiratory health impacts; (3) restricting plastic usage, such as banning microbeads in cosmetics and limiting non-biodegradable cigarette filters; (4) enhancing recycling methods and developing biodegradation or enzymatic degradation technologies²³¹; (5) increasing public awareness and promoting a healthy, eco-friendly lifestyle by reducing MP intake (e.g., drinking plain water and limiting takeout consumption)²³²; and (6) establishing standardized atmospheric MP monitoring systems and defining health guidelines based on comprehensive toxicity and exposure data.

Conclusion

In summary, as plastic production and usage continue to rise, associated health risks are also increasing. The respiratory toxicity of MPs and NPs warrants greater scientific attention. This review synthesizes current epidemiological evidence and laboratory findings, highlighting adverse effects of MPs and NPs on pulmonary health. Exposure to these particles is linked to various respiratory conditions, including pulmonary emphysema, pneumonia, COPD, asthma, and structural lung damage. Notably, smaller particle sizes, aged plastics, and specific chemical modifications are associated with greater respiratory toxicity. However, small-scale population studies, limitations of exposure assessment methods, and insufficient environmental realism in laboratory studies introduce uncertainties in evaluating respiratory risks. This emerging field requires multifaceted collaboration to accurately evaluate these risks and implement effective policies to protect environmental and public respiratory health.

Funding and Acknowledgments

The authors would like to acknowledge financial support from the Henan Province Medical Science and Technology Public Relations Plan Province Department joint construction project (grant LHGJ20230303, LHGJ20240287), the China Postdoctoral Science Foundation (grant 2024M752963), and the Key Research Project of Higher Education Institutions in Henan Province (grant 25A330002). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author contributions

Literature search, Yaxin Guo, Yao Guo, X.D., Y.Y., D.D., and J.Y.; writing, Yaxin Guo, Yao Guo, Y.Y., and J.Y.; data collection, Yaxin Guo, Yao Guo, X.D., Y.Y., and D.D.; figures, Yaxin Guo, Yao Guo, X.D., D.D., K.G., and R.M.; validation, Yaxin Guo and Yao Guo.; conceptualization, Z.W. and H.L.; data curation, Z.W. and H.L.; project administration, H.L. All authors contributed to the manuscript and approved the final version.

Declaration of interests

The authors declare no competing interests.

Published Online: February 6, 2026