Mater Today Bio. 2026 Aug 18;40:103583. doi: 10.1016/j.mtbio.2026.103583. eCollection 2026 Oct.

ABSTRACT

TLR4 activation and the cascade of neutrophil extracellular trap (NET) formation exacerbate excessive inflammation and organ damage in the pathogenesis of acute lung injury (ALI), yet effective pharmacological interventions remain unavailable. Nanoaggregates derived from natural products offer promising avenue by leveraging synergistic anti-inflammatory effects. In this study, we surprisingly discovered that leonurine and ursolic acid spontaneously self-assemble into nanoparticles (LUNP) through non-covalent interactions, achieving a drug loading capacity of 100%. The LUNP platform exhibits superior biophysical properties, including enhanced mucus penetration, pH-responsive drug release, improved cellular uptake, and prolonged retention within inflamed lung tissue. Mechanistically, LUNP ameliorates ALI by dampening TLR4/MyD88/NF-κB-driven inflammatory activation, thereby remodeling the microenvironment to limit NOX4-PAD4-mediated NET formation. Notably, inhalational LUNP exhibits outstanding biosafety with minimal off-target distribution. Overall, this work introduces a synergistic self-assembled nanoplatform for precise pulmonary intervention in ALI, showcasing its ability to safely and effectively orchestrate the coordinated modulation of multiple pathological pathways. In summary, by inhibiting both TLR4 activation and NET formation, the synergistic LUNP platform offers an efficient, safe, and easily accessible therapeutic strategy for ALI, providing a promising solution for clinical translation.

PMID:42750707 | PMC:PMC13577835 | DOI:10.1016/j.mtbio.2026.103583

J Thorac Oncol. 2026 Sep 16:104204. doi: 10.1016/j.jtho.2026.104204. Online ahead of print.

ABSTRACT

BACKGROUND: Early-stage EGFR-mutant lung adenocarcinoma (LUAD) demonstrates heterogeneous outcomes after curative surgery, yet adjuvant treatment decisions are guided by pathological stage alone. Following the ADAURA trial, adjuvant osimertinib is the standard of care for resected stage IB-IIIA EGFR-mutant LUAD; however, real-world data demonstrate that up to 40% of patients remain disease-free at five years without adjuvant osimertinib, underscoring the need for improved risk stratification.

PATIENTS AND METHODS: We performed integrated clinical, genomic and transcriptomic profiling of 400 patients with resected stage IA-IIIA EGFR-mutant LUAD. EGFR-mutant recurrence risk models integrating clinical, genomic and transcriptomic data were developed and validated across one internal and three external cohorts.

RESULTS: Genomic instability, including TP53 co-mutations, copy number alterations and APOBEC-associated mutational signatures, increased with pathological stage. RBM10 co-mutations were enriched in tumours with L858R mutations and correlated with upregulation of WNT signalling and epithelial-mesenchymal transition. Transcriptomic features outperformed clinical or genomic variables alone in predicting recurrence risk, and a multi-omic model demonstrated superior and reproducible performance, achieving a median concordance index of 75.4% across four independent validation cohorts. The multi-omic model stratified recurrence risk within individual pathological stages, including stage I disease, and identified patients most likely to benefit from adjuvant EGFR TKI.

CONCLUSIONS: These findings define the molecular heterogeneity of early-stage EGFR-mutant LUAD and support multi-omic risk stratification to inform adjuvant EGFR TKI decisions beyond pathological stage. Prospective validation in larger cohorts will be required to confirm these findings.

PMID:42749051 | DOI:10.1016/j.jtho.2026.104204

Nat Genet. 2026 Sep 15. doi: 10.1038/s41588-026-02751-3. Online ahead of print.

ABSTRACT

Inflammation accelerates evolutionary dynamics of hematopoietic stem cells (HSCs) in clonal hematopoiesis and myeloid neoplasms. We studied HSCs, progenitors and immune cells from patients with myeloproliferative neoplasms at baseline and following interferon-α (IFNα) treatment, the only therapy to deplete mutated stem cells. We deployed single-cell multiomics methods that distinguish the IFNα effects on mutated stem cells from the admixed wild-type HSCs, with respect to their differentiation, transcriptomes, immunophenotypes and chromatin accessibility. IFNα simultaneously activated HSCs into two polarized states: a lymphoid progenitor expansion associated with an anti-inflammatory state and an inflammatory myeloid progenitor state derived from HSCs. The augmented lymphoid differentiation balanced the typical myeloproliferative-neoplasm-induced myeloid bias, associated with normalized blood counts. Somatic mutations modified the effects of IFNα on HSC differentiation and cell cycle entry rates. Clonal fitness upon IFNα exposure was due to resistance of CALR- or JAK2-mutated stem cells to differentiate into inflammatory myeloid progenitors.

PMID:42745000 | DOI:10.1038/s41588-026-02751-3