Respiratory diseases impose a substantial global burden; however, early diagnosis, disease-activity monitoring, and the clinical translation of nucleic acid therapeutics are constrained by the lack of robust biomarkers and efficient delivery systems. This narrative review focuses on four classes of RNA—messenger RNA (mRNA), circular RNA (circRNA), small interfering RNA (siRNA), and microRNA (miRNA)—using exosomes as a representative subtype of extracellular vesicles (EVs) to discuss EV biogenesis, transport, uptake, and engineered cargo loading. We summarize the diagnostic and therapeutic applications of EV-associated nucleic acids in chronic or non-severe respiratory diseases, including asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and cystic fibrosis, as well as in severe acute conditions such as acute respiratory distress syndrome and severe pneumonia. Biofluid-derived EV-associated RNAs can reflect inflammation, immune dysregulation, epithelial injury, infection, and fibrosis, supporting their potential use in disease classification, monitoring, and prognostic assessment. Natural EVs may modulate inflammation and tissue repair through their endogenous cargo, while engineered EVs can deliver therapeutic nucleic acids to exert anti-inflammatory, anti-infective, antifibrotic, and barrier-restorative effects. However, clinical translation is limited by non-standardized isolation and characterization methods, product heterogeneity, variable cargo loading, and insufficient stability and quality-control frameworks. Continued advances in EV isolation, characterization, nucleic acid loading, potency assessment, and manufacturing control are required to realize the diagnostic and therapeutic potential of EV-associated nucleic acids in respiratory diseases.

Background/Objectives: Stress-enhanced fear learning (SEFL) tests whether severe stress amplifies a later, separate fear-learning episode. Although SEFL studies commonly report increased freezing, its overall effect size, robustness, protocol-level variation, and translational interpretation have not been systematically quantified. This review evaluated SEFL as a focused paradigm of stress-induced fear-learning sensitization rather than as a comprehensive model of posttraumatic stress disorder (PTSD). Methods: Web of Science Core Collection, PubMed, Embase, and Scopus were searched from inception to June 2026. Eligible studies used an SEFL-related procedure, included independent stress-exposed and control groups, and reported extractable freezing outcomes during later fear testing. Hedges’ g values were pooled using restricted maximum-likelihood random-effects models. We also examined exploratory subgroup analyses, sensitivity analyses, and small-study-effect assessments. Results: Twenty-five studies comprising 49 comparisons were included. Stress-exposed animals showed higher freezing than controls during later fear testing (Hedges’ g = 1.71, 95% CI [1.38, 2.04], p < 0.001). Heterogeneity was substantial (I² = 81.91%, τ² = 1.07), and the 95% prediction interval crossed zero (−0.40 to 3.82), indicating that SEFL is not protocol-invariant. Exploratory subgroup analyses suggested protocol- and sample-level variation, particularly by species, strain, stress method, testing interval, and stress type. Contextual-fear-conditioning-only, study-level, non-footshock-exclusion, and leave-one-out sensitivity analyses supported the overall positive effect, although possible small-study effects should be considered when interpreting the pooled estimate. Conclusions: SEFL is best interpreted as a protocol-sensitive behavioral neuroscience paradigm for studying stress-enhanced later fear learning after severe stress rather than as a broad PTSD model. The current evidence supports a large average freezing-defined SEFL effect, but the marked heterogeneity and limited intervention-related evidence indicate that the paradigm should be interpreted with attention to protocol conditions and translational scope.