Nanodelivery systems-empowered therapies of idiopathic pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal interstitial lung disease of undefined etiology. In recent years, its global incidence has shown an upward trend, with a median survival of approximately 3–5 years after diagnosis. Currently, clinical treatment outcomes for this disease remain limited. Approved therapeutic agents are nintedanib, pirfenidone, and nerandomilast, all of which are predominantly administered orally. The oral route renders drugs susceptible to degradation in the gastrointestinal tract, leading to reduced drug bioavailability and limited therapeutic efficacy. In this work, we believe that nanodelivery systems (NDSs) represent a promising approach to address the limitations of traditional therapies. Most importantly, we emphasized that inhalation NDSs should be prioritized to enhance the accumulation efficiency of targeted drugs at pulmonary lesion sites. Collectively, this study aims to provide insights into the developmental prospects of NDSs for IPF, paving the way for more efficient and personalized therapeutic approaches to enhance treatment efficacy while minimizing side effects.

Keywords

idiopathic pulmonary fibrosis / nanodelivery systems / inhalable nanoparticles

References

[1] Poon M, Lorrain K, Broadhead A, Stebbins K, Bagnol D, Edu G, et al. The LPAR1 antagonist, PIPE-791 produces antifibrotic effects in models of lung fibrosis. Respir Res. 2025; 26: 265.

[2] Göktürk K, Tülek B, Kanat F, Maçin S, Arslan U, Shahbazova M, et al. Gut microbiota profiles of patients with idiopathic pulmonary fibrosis. Exp Lung Res. 2024; 50: 278-89.

[3] Lee D, Kong B, Kwak G, Kang B, Swaby C, Fanaroff R, et al. Clinically translatable anti-fibrotic nanosuspension for inhaled treatment of idiopathic pulmonary fibrosis. Drug Deliv Transl Res. 2026; 16: 1581-91.

[4] Pan L, Cheng Y, Yang W, Wu X, Zhu H, Hu M, et al. Nintedanib Ameliorates Bleomycin-Induced Pulmonary Fibrosis, Inflammation, Apoptosis, and Oxidative Stress by Modulating PI3K/Akt/mTOR Pathway in Mice. Inflammation. 2023; 46: 1531-42.

[5] Kim CG, Jang M, Oh C, Jeon OH, Choi BH, Kim K, et al. Pulmonary surfactant-based pirfenidone-loaded nanovesicles for inhalation therapy of idiopathic pulmonary fibrosis. J Control Release. 2025; 385: 114005.

[6] Richeldi L, Azuma A, Cottin V, Kreuter M, Maher TM, Martinez FJ, et al.; FIBRONEER-IPF Trial Investigators. Nerandomilast in Patients with Idiopathic Pulmonary Fibrosis. N Engl J Med. 2025; 392: 2193-202.

[7] Luo Q, Xie Y, Xu J, Ren Y, Xiong S, Zhang H, et al. Recombinant PD1 liposome loading nintedanib for pulmonary fibrosis therapy in mice. Chem Eng J. 2025; 525: 169905.

[8] Zhao T, Gong B, Luo S, Zhang R, Zhang L, Huang Y, et al. A fibroblastic foci-targeting and hypoxia-cleavable delivery system of pirfenidone for the treatment of idiopathic pulmonary fibrosis. Acta Biomater. 2023; 167: 574-82.

[9] Sheridan C. FDA approves new mechanism to treat idiopathic pulmonary fibrosis, expanding limited arsenal. Nat Biotechnol. 2025; 43: 1747-50.

[10] Qiu Y, Ye W. Therapeutic efficacy of pirfenidone and nintedanib in pulmonary fibrosis; a systematic review and meta-analysis. Ann Thorac Med. 2025; 20: 145-52.

[11] Maher TM, Assassi S, Azuma A, Cottin V, Hoffmann-Vold AM, Kreuter M, et al. Nerandomilast in Patients with Progressive Pulmonary Fibrosis. N Engl J Med. 2025; 392: 2193-202.

[12] Zang C, Zheng Y, Wang Y, Li L. The effects and safety of pirfenidone in the treatment of idiopathic pulmonary fibrosis: a meta-analysis and systematic review. Eur J Med Res. 2021; 26: 129.

[13] Bonella F, Cottin V, Valenzuela C, Wijsenbeek M, Voss F, Rohr KB, et al. Meta-Analysis of Effect of Nintedanib on Reducing FVC Decline Across Interstitial Lung Diseases. Adv Ther. 2022; 39: 3392-402.

[14] Furuya K, Sakamoto S, Shimizu H, Sekiya M, Kinoshita A, Isshiki T, et al. Pirfenidone for acute exacerbation of idiopathic pulmonary fibrosis: A retrospective study. Respir Med. 2017; 126: 93-9.

[15] Albera C, Costabel U, Fagan EA, Glassberg MK, Gorina E, Lancaster L, et al. Efficacy of pirfenidone in patients with idiopathic pulmonary fibrosis with more preserved lung function. Eur Respir J. 2016; 48: 843-51.

[16] Huh J, Lee JH, Song JW. Efficacy and safety of combination therapy with pirfenidone and nintedanib in patients with idiopathic pulmonary fibrosis. Front Pharmacol. 2023; 14: 1301923.

[17] Zhao C, Xiao A, Chen C, Mu W, Li W, Chang L. Nanotechnology for diagnosis and therapy of idiopathic pulmonary fibrosis: Recent advances and future perspectives. Nano Today. 2026; 66: 102889.

[18] Wiertz IA, Wuyts WA, van Moorsel CHM, Vorselaars ADM, van Es HW, van Oosterhout MFM, et al. Unfavourable outcome of glucocorticoid treatment in suspected idiopathic pulmonary fibrosis. Respirology. 2018; 23: 311-7.

[19] Zhang X, Zhang L, Tian J, Li Y, Wu M, Zhang L, et al. The application and prospects of drug delivery systems in idiopathic pulmonary fibrosis. Biomater Adv. 2025; 168: 214123.

[20] Kaur R, Shaikh TB, Sripadi HP, Kuncha M, Sarathi UVRV, Kulhari H, et al. Nintedanib solid lipid nanoparticles improve oral bioavailability and ameliorate pulmonary fibrosis in vitro and in vivo models. Int J Pharm. 2024; 649: 123644.

[21] Dong S, Fang H, Zhu J, Wu Z, Liu Y, Zhu J, et al. Inhalable siRNA Targeting IL-11 Nanoparticles Significantly Inhibit Bleomycin-Induced Pulmonary Fibrosis. ACS Nano. 2025; 19: 2742-58.

[22] Chen Z, Yang J, Zhang Q, Zeng W, Liu Y, Hu W, et al. Inhalable myofibroblast targeting nanoparticles for synergistic treatment of pulmonary fibrosis. Sci Adv. 2025; 11: eadv9571.

[23] Ding L, Tang S, Tang W, Mosley DD, Yu A, Sil D, et al. Perfluorocarbon Nanoemulsions Enhance Therapeutic siRNA Delivery in the Treatment of Pulmonary Fibrosis. Adv Sci (Weinh). 2022; 9: e2103676.

[24] Ghumman M, Dhamecha D, Gonsalves A, Fortier L, Sorkhdini P, Zhou Y, et al. Emerging drug delivery strategies for idiopathic pulmonary fibrosis treatment. Eur J Pharm Biopharm. 2021; 164: 1-12.

[25] Wan Q, Zhang X, Zhou D, Xie R, Cai Y, Zhang K, et al. Inhaled nano-based therapeutics for pulmonary fibrosis: recent advances and future prospects. J Nanobiotechnology. 2023; 21: 215.

[26] Ouyang S, Lu P, Li J, Jin H, Wu W, Luo R, et al. Inhaled tea polyphenol-loaded nanoparticles coated with platelet membranes largely attenuate asthmatic inflammation. Respir Res. 2024; 25: 311.

[27] Pan X, Wu N, Tian S, Guo J, Wang C, Sun Y, et al. Inhalable MOF-Derived Nanoparticles for Sonodynamic Therapy of Bacterial Pneumonia. Adv Funct Materials. 2022; 32: 2112145.

[28] Guo M, Liang Y, Zhang M, Fu Y, Luo P, Huang Y, et al. Lysosome-hijacking inhalable nanomimosa enhances ferroptosis for lung cancer therapy. J Control Release. 2025; 386: 114101.

[29] Peng Y, Wang ZN, Xu AR, Fang ZF, Chen SY, Hou XT, et al. Mucus Hypersecretion and Ciliary Impairment in Conducting Airway Contribute to Alveolar Mucus Plugging in Idiopathic Pulmonary Fibrosis. Front Cell Dev Biol. 2022; 9: 810842.

[30] Liang M, Ruan S, Wang Q, Cheng Y, Li J, Wang C, et al. A mitochondria-targeted fluoropolymer nanoparticle with inherent mitophagy-inducing and red fluorescence properties for treatment of atherosclerosis. Nat Commun. 2025; 16: 9845.

[31] Ren H, Han L, Zhang L, Zhao Y, Lei C, Xiu Z, et al. Inhalable responsive polysaccharide-based antibiotic delivery nanoparticles to overcome mucus barrier for lung infection treatment. Nano Today. 2022; 44: 101489.

[32] Younis MA, Tawfeek HM, Abdellatif AAH, Abdel-Aleem JA, Harashima H. Clinical translation of nanomedicines: Challenges, opportunities, and keys. Adv Drug Deliv Rev. 2022; 181: 114083.