Nanomedicine-enabled ferroptosis intervention:from antitumor effects to immune remodeling in lung diseases

Ferroptosis, a regulated cell death (RCD) process driven by iron-dependent lipid peroxidation, has emerged as a pivotal focus in recent therapeutic research for lung diseases. This comprehensive review synthesizes the latest breakthroughs in ferroptosis-based therapy development, highlighting the transformative potential of nanomedicine in the precise regulation of this cell death pathway-with particular emphasis on the critical role of immune remodeling in achieving optimal therapeutic outcomes. The ferroptosis execution cascade is first delineated, alongside its mechanistic differences from disulfidptosis: a novel RCD modality that shares key regulatory nodes with ferroptosis, yet possesses distinct execution mechanisms centered on sulfur metabolism and unique translational value in lung cancer. Central to this discussion is the lung-specific ferroptosis paradox: while targeted ferroptosis induction effectively eradicates therapy-resistant lung tumors, uncontrolled activation in alveolar epithelial cells (AECs) may initiate and exacerbate interstitial lung disease (ILD). Lung cancer-specific ferroptosis vulnerabilities are further characterized, including differential sensitivity between major non-small cell lung cancer (NSCLC) subtypes and unique therapeutic windows in high-frequency mutant subtypes (e.g., KEAP1-mutant lung adenocarcinoma). Promising therapeutic strategies focus on nanomedicine-driven approaches, including tumor-targeted nanocarriers, stimuli-responsive systems, and biomimetic vesicles, that enable spatiotemporally precise control of ferroptosis, thereby maximizing antitumor efficacy while mitigating the risks of immune dysregulation and off-target pulmonary toxicity. The mechanisms by which nanomedicines overcome the core clinical bottlenecks of ferroptosis therapy are elaborated, alongside a systematic comparison of intravenous, intratumoral, and inhalation administration routes tailored for lung disease interventions. The bidirectional crosstalk between ferroptosis and antitumor immunity within the lung tumor microenvironment (TME) is systematically dissected, with detailed characterization of how nanomedicine-mediated ferroptosis modulation optimizes this crosstalk to drive therapeutic pulmonary immune remodeling. Finally, key future directions for the advancement of precision ferroptosis medicine are outlined, including spatiotemporally controlled ferroptosis activation, biomarker-driven patient stratification panels, and rational strategies to balance therapeutic efficacy and pulmonary safety throughout clinical translation.