Over the past decades, lipid‐based nanoparticle drug delivery systems (DDS) have caught the attention of researchers worldwide, encouraging the field to rapidly develop improved ways for effective drug delivery. One of the most prominent examples is liposomes, which are spherical shaped artificial vesicles composed of lipid bilayers and able to encapsulate both hydrophilic and hydrophobic materials. At the same time, biological nanoparticles naturally secreted by cells, called extracellular vesicles (EVs), have emerged as promising more complex biocompatible DDS. In this review paper, the differences and similarities in the composition of both vesicles are evaluated, and critical mediators that affect their pharmacokinetics are elucidate. Different strategies that have been assessed to tweak the pharmacokinetics of both liposomes and EVs are explored, detailing the effects on circulation time, targeting capacity, and cytoplasmic delivery of therapeutic cargo. Finally, whether a hybrid system, consisting of a combination of only the critical constituents of both vesicles, could offer the best of both worlds is discussed. Through these topics, novel leads for further research are provided and, more importantly, gain insight in what the liposome field and the EV field can learn from each other.

A key aspect for successful drug delivery via lipid‐based nanoparticles is their internalization in target cells. Two prominent examples of such drug delivery systems are artificial phospholipid‐based carriers, such as liposomes, and their biological counterparts, the extracellular vesicles (EVs). Despite a wealth of literature, it remains unclear which mechanisms precisely orchestrate nanoparticle‐mediated cargo delivery to recipient cells and the subsequent intracellular fate of therapeutic cargo. In this review, internalization mechanisms involved in the uptake of liposomes and EVs by recipient cells are evaluated, also exploring their intracellular fate after intracellular trafficking. Opportunities are highlighted to tweak these internalization mechanisms and intracellular fates to enhance the therapeutic efficacy of these drug delivery systems. Overall, literature to date shows that both liposomes and EVs are predominantly internalized through classical endocytosis mechanisms, sharing a common fate: accumulation inside lysosomes. Studies tackling the differences between liposomes and EVs, with respect to cellular uptake, intracellular delivery and therapy efficacy, remain scarce, despite its importance for the selection of an appropriate drug delivery system. In addition, further exploration of functionalization strategies of both liposomes and EVs represents an important avenue to pursue in order to control internalization and fate, thereby improving therapeutic efficacy.

Currently, there is no pharmacological treatment targeting defective tissue repair in chronic disease. Here, we used a transcriptomics-guided drug target discovery strategy using gene signatures of smoking-associated chronic obstructive pulmonary disease (COPD) and from mice chronically exposed to cigarette smoke, identifying druggable targets expressed in alveolar epithelial progenitors, of which we screened the function in lung organoids. We found several drug targets with regenerative potential, of which EP and IP prostanoid receptor ligands had the most profound therapeutic potential in restoring cigarette smoke–induced defects in alveolar epithelial progenitors in vitro and in vivo. Mechanistically, we found, using single-cell RNA sequencing analysis, that circadian clock and cell cycle/apoptosis signaling pathways were differentially expressed in alveolar epithelial progenitor cells in patients with COPD and in a relevant model of COPD, which was prevented by prostaglandin E2 or prostacyclin mimetics. We conclude that specific targeting of EP and IP receptors offers therapeutic potential for injury to repair in COPD.

One of the main pathological features of chronic obstructive pulmonary disease (COPD) is the loss of functional alveolar tissue as a consequence of impaired regenerative capacities (emphysema). Recent research suggests that the secretome from mesenchymal cells, particularly extracellular vesicles (EVs), may possess regenerative properties beneficial for lung repair. However, the regenerative potential of the soluble factors (SFs) within the secretome remains largely unexplored in COPD. To this extent, we purified EVs and SFs secreted by lung fibroblasts to generate EV-enriched and SF-enriched fractions, and evaluated their effects on elastase-induced lung injury in both precision-cut lung slices (PCLS) and a mouse model. EV- and SF-enriched fractions were concentrated and purified from the conditioned medium of cultured MRC-5 lung fibroblasts using a combination of ultrafiltration and size exclusion chromatography, and were subsequently characterized according to the MISEV guidelines. Treatment with EV- or SF-enriched concentrates prevented and improved elastase-induced emphysema in PCLS, leading to reduced lung injury and upregulated markers of alveolar epithelial cells (aquaporin 5 and surfactant protein C), indicating potential parenchymal regeneration. Accordingly, prophylactic intratracheal treatment with lung fibroblast-derived EV- and SF-enriched concentrates in vivo attenuated elastase-induced lung tissue destruction, improved lung function, and enhanced gene expression of alveolar epithelial cell markers. Here, alveolar repair not only serves the purpose of facilitating gas exchange, but also by reinstating the essential parenchymal tethering required for optimal airway mechanics. In conclusion, this study highlights the therapeutic potential of both lung fibroblast-derived EV- and SF-enriched concentrates for the treatment of lung injury and emphysema.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide, with a significant impact on low‐ and middle‐income countries, making it a critical challenge for global health equity and sustainable development goals. Extracellular vesicles (EVs) are emerging as a promising treatment for COPD, but conventional storage at −80 °C limits their global accessibility. This study explores alternative storage methods to enhance EV stability and accessibility, particularly in low‐resource settings. EVs from lung fibroblasts are subjected to freezing, freeze drying, and spray drying with inulin or mannitol. The biophysical properties are evaluated by their capacity to support lung organoid formation. Inulin proves effective in stabilizing EVs, maintaining functionality after freezing at −20 °C for 12 weeks. Freeze drying with inulin preserves EV stability at 20 °C and 43% relative humidity. In contrast, EVs with mannitol exhibit aggregation and reduce bio‐functionality. Additionally, spray drying EVs with inulin and leucine produces a dry powder suitable for inhalation, maintaining biophysical properties and functionality for 12 weeks. The powder demonstrates efficient lung deposition using the Cyclops inhaler. These findings suggest inulin as a stabilizer for EVs, eliminating the need for ultra‐low temperature storage and improving the practicality of EV‐based inhalable therapies.