The pulmonary system is a critical interface between the body and the external environment and is therefore vulnerable to environmental, infectious, and genetic insults. Conventional gene and drug therapies face multiple limitations in this context, including safety concerns with viral vectors, instability of therapeutic agents, suboptimal cellular internalization, and inadequate tissue- and cell-specific targeting. The reviewed work frames precision nanomedicine as a strategy to address these shortcomings by tailoring nanoparticle carriers to the unique demands of respiratory therapy and disease biology.
Nanoparticle-based delivery platforms offer several mechanistic advantages that can mitigate the weaknesses of traditional approaches. Specifically, nanoparticles can enhance therapeutic stability and bioavailability, allow for controlled release of payloads, facilitate cellular uptake and endosomal escape, and enable targeted delivery to defined lung compartments. These functional capabilities position nanoparticles as versatile vehicles for both small-molecule drugs and nucleic acid–based therapeutics in pulmonary applications.
Successful pulmonary nanomedicine depends on careful control of key physicochemical properties. Particle size, surface chemistry, charge, rigidity/flexibility, and biodegradability all influence deposition in the respiratory tract, mucociliary clearance, cellular uptake, and immune recognition. The review emphasizes matching nanoparticle design to the target lung compartment and intended route of delivery to optimize tissue penetration, retention time, and therapeutic effect while minimizing off-target exposure.
Targeting approaches discussed include surface functionalization with ligands for cell-specific receptors, stimuli-responsive materials that release payloads under selected physiological conditions, and designs that enhance endosomal escape for intracellular delivery. Advanced engineering of nanoparticle surfaces and core–shell architectures can improve selectivity for particular cell types within the lung, enabling more precise modulation of disease processes while reducing systemic toxicity.
Given the lung’s unique architecture and physiology, the review compares pulmonary (local) delivery and systemic administration, outlining advantages and limitations of each route. Pulmonary delivery can provide high local concentrations and reduced systemic exposure, but must overcome mucosal barriers and lung clearance mechanisms. Systemic delivery may reach lung vasculature and parenchymal targets indirectly, but is subject to distribution to nonpulmonary tissues and different clearance pathways. The authors emphasize that route selection should be context-specific and guided by target location, disease pathophysiology, and nanoparticle properties.
The review surveys nanoparticle design and therapeutic applications across a broad spectrum of pulmonary diseases. Disease areas covered include pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), infectious diseases of the lung, pulmonary vascular disease, cystic fibrosis, asthma, lung cancers, and neonatal pulmonary disorders. For each disease class, the review links pathological mechanisms to rational nanocarrier strategies—for example, enhancing penetration in fibrotic tissue, overcoming mucus barriers in cystic fibrosis, or delivering targeted anticancer payloads to tumor microenvironments. Rather than focusing on a single nanoparticle type or isolated pathology, the work synthesizes cross-disease design principles.
Several translational impediments are highlighted. Biological barriers—such as mucus, surfactant interactions, immune recognition, and clearance pathways—can limit effective deposition and retention. Long-term safety concerns include potential chronic inflammatory responses and off-target effects. Manufacturing hurdles involve reproducible large-scale production, quality control of complex particle architectures, and ensuring stability and batch consistency. The review underscores that addressing these challenges is essential for progressing from preclinical promise to clinical utility.
The review evaluates the current status of clinical trials for respiratory nanomedicines and identifies persistent gaps between preclinical advances and clinical translation. While clinical evaluation is ongoing in the field, the authors note translational challenges that slow progress, including biological barriers, safety and durability of response, and manufacturing scalability. Specific trial-level details were not reported in the abstract and therefore are not summarized here.
To accelerate clinical translation, the review proposes interdisciplinary strategies that integrate nanoparticle bioengineering with disease-specific physiology, improved preclinical models that better recapitulate human lung biology, and coordinated efforts to address manufacturing and regulatory pathways. The authors advocate for context-specific delivery strategies informed by lung architecture, targeted design of nanocarriers to disease mechanisms, and careful evaluation of long-term safety. These combined approaches aim to move precision nanocarriers from experimental platforms to clinically actionable therapies for a range of pulmonary disorders.
(© 2026. The Author(s). The authors declare no competing interests.)