Pulmonary fibrosis (PF) is a continual, progressive interstitial lung illness characterised by the irregular scarring of lung tissue [1]. This pathological course of ends in impaired gasoline change, dyspnea, decreased train tolerance, and diminished high quality of life [2]. The illness presents a multifactorial etiology, encompassing environmental exposures [3], [4], [5], [6] (e.g. smoking [7], asbestos [8], silica [9]), medical elements (e.g., drug-induced toxicity from bleomycin [10], amiodarone [11], methotrexate [12], or the unintended effects of radiation remedy [13]), genetic predispositions (e.g., mutations related to surfactant protein or telomerase genes [14], [15]), and systemic illnesses equivalent to autoimmune situations and viral infections like COVID-19, abnormalities within the lung microbiome, or immune dysregulation [16], [17], [18], [19].
Following publicity to dangerous stimuli or harm, the lungs usually expertise oxidative stress and inflammatory responses. Throughout this course of, pathways equivalent to nuclear factor-kappa B (NF-κB), and mitogen-activated protein kinase (MAPK) are activated, resulting in the manufacturing of inflammatory cytokines, together with interleukins (IL-1β, IL-6, IL-8, and so on.), tumor necrosis factor-α (TNF-α), connective tissue progress issue (CTGF), reworking progress factor-beta (TGF-β), and platelet-derived progress issue (PDGF), amongst others [20], [21], [22], [23]. These cytokines recruit inflammatory cells, equivalent to macrophages, to the location of harm through autocrine and paracrine mechanisms. The recruited inflammatory cells launch further inflammatory mediators and cytokines, which additional stimulate the proliferation and differentiation of fibroblasts, in addition to the activation of myofibroblasts, contributing to the restore of lung harm [24], [25]. Throughout this stage, epithelial cells could lose their unique traits and features, present process epithelial-to-mesenchymal transition (EMT) [26]. Insufficient decision of the inflammatory response disrupts the fragile steadiness of the restore course of, driving the overactivation of myofibroblasts and extreme deposition of extracellular matrix (ECM) proteins. This pathological reworking of lung tissue culminates within the formation of fibrotic scars, progressively impairing lung operate and contributing to the onset of PF. Fig. 1 offers an built-in view of those molecular mechanisms, showcasing the advanced interaction between mobile harm, inflammatory signaling, and fibrotic reworking. A deeper understanding of those processes is important for the event of progressive, focused therapies for PF.
PF is related to poor prognosis, posing a major risk to human well being and high quality of life [27]. Conventional remedies for PF primarily embody glucocorticoids, administered orally or intravenously (e.g., prednisone, methylprednisolone), and different immunosuppressive brokers, equivalent to cyclophosphamide, mycophenolate mofetil (MMF), azathioprine, and rituximab. Whereas these therapies can management irritation and gradual fibrosis development, they’ve notable limitations. These embody immune suppression resulting in opposed results equivalent to osteoporosis, elevated fracture danger, hyperglycemia, diabetes, and heightened susceptibility to infections. Different unintended effects embody gastrointestinal discomfort and neurological issues (Desk 1) [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45]. Moreover, these remedies lack sturdy proof from randomized managed trials [30], and extra importantly, they can’t reverse PF development. Particularly, pirfenidone and nintedanib are the one FDA-approved antifibrotic medicine for PF [31]. Though these medicine gradual illness development, they don’t treatment the situation or fully alleviate signs. Moreover, their use is related to important unintended effects, together with nausea, vomiting, urge for food loss, pores and skin rashes, erythema, pruritus, liver dysfunction, and hypertension [32], [33], [34]. These limitations spotlight the necessity for progressive therapeutic methods to enhance outcomes for PF sufferers.
To reinforce therapeutic outcomes and enhance sufferers’ high quality of life, it’s important to repeatedly discover novel therapeutic methods and strategies. Inhalation remedy, which administers medicine in particular kinds equivalent to aerosols, dry powders, nebulized options, or suspensions through the respiratory tract, straight targets the mucosa or alveoli of the respiratory system, demonstrating important benefits in treating PF. Critically, inhalation remedy permits medicine in particulate kind to be straight inhaled into the terminal bronchioles or alveoli, growing native drug focus and enabling direct motion on the goal organs. This methodology bypasses the necessity for oral medicine to be absorbed and distributed by way of the digestive system, thereby decreasing drug loss throughout supply [45]. Notably, because the drug acts straight on the respiratory tract, inhalation remedy usually has a extra speedy onset of motion [46]. Moreover, the drug particles in inhalation remedy may be utilized on to the lesions in lung cells, thus requiring a considerably decrease dose to realize the identical therapeutic impact in comparison with oral or injectable kinds. This helps reduce drug accumulation within the physique, reduces systemic distribution, and lowers the drug’s poisonous results on the liver and different organs [47]. Extra importantly, inhalation remedy is a non-invasive remedy methodology that doesn’t require surgical procedures or injections, thereby decreasing affected person ache and discomfort. This non-invasive nature makes inhalation remedy extra acceptable to sufferers [48]. Inhalation remedy additionally provides financial advantages equivalent to shorter hospital stays and price financial savings, establishing it as a frontline basic remedy methodology [49]. A notable instance is the inhaled formulation of pirfenidone (AP01), which is at present being evaluated for security and efficacy in sufferers with progressive PF in a scientific trial (NCT06329401), reflecting the rising curiosity in inhalation-based therapeutic methods for PF administration. Scientific insights from pediatric respiratory drugs have additionally highlighted the pressing want for non-invasive, lung-targeted therapies with improved security profiles, significantly in susceptible populations equivalent to youngsters.
Regardless of its benefits, inhalation remedy faces notable challenges, together with variability in lung deposition effectivity, dependence on affected person respiratory patterns, machine efficiency, and affected person compliance [50], [51]. Moreover, many potential therapeutic brokers exhibit poor water solubility or stability within the respiratory tract atmosphere, and their inherent potential to beat lung limitations is proscribed. Consequently, these medicine exhibit low bioavailability and effectiveness when administered through inhalation remedy, thereby proscribing their potential functions on this therapeutic method [52], [53]. To deal with these limitations, inhalable nanomedicine supply methods provide promising options. By leveraging nanotechnology, uncooked medicine or lively substances are processed into nanoscale particles or mixed with nanocarriers to enhance stability, dispersion, and bioavailability. This allows deeper penetration of lung limitations and extra exact concentrating on of lesion websites [54], [55]. Nanomedicine additionally offers alternatives for innovation by permitting the design of inhaled medicine with tailor-made options, equivalent to concentrating on, sustained launch, and environmental responsiveness [56], thus overcoming the efficacy and security limitations of conventional therapies [57]. This additionally expanded their therapeutic potential for PF.
Regardless of these developments, the distinctive physiological and protection mechanisms of the lungs, such because the mucus barrier, alveolar macrophage (AM) clearance, and the affect of pulmonary surfactants, pose important challenges for inhalable nanomedicine supply [58], [59]. A deep understanding of those limitations is essential for optimizing supply effectivity and therapeutic outcomes. This assessment highlights the most recent progress in inhalable nanomedicine supply methods, with a give attention to overcoming lung limitations and advancing PF remedy. By integrating insights from nanotechnology and pulmonary biology, these improvements have the potential to redefine therapeutic paradigms, providing new hope for sufferers affected by this debilitating illness.
