Stimuli-responsive nanomedicines for lung cancer therapy: Design strategies, advances, challenges, and future directions

Lung cancer (LC) remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) posing major therapeutic challenges due to multidrug resistance, systemic toxicity, and poor tumor selectivity of conventional treatments. Stimuli-responsive nanomedicines (SRNs) have emerged as innovative platforms enabling spatiotemporally controlled and tumor-specific drug delivery by exploiting intrinsic biological cues (pH, redox imbalance, enzyme overexpression) or externally applied triggers (magnetic fields, electric fields, ultrasound, near-infrared light, X-rays). This review critically evaluates the design, therapeutic performance, and translational relevance of emerging SRN platforms—including polymeric nanoparticles, micelles, lipid-based carriers, metal–organic frameworks (MOFs), nanoclusters, and hybrid core–shell architectures—highlighting their targeting strategies, physicochemical properties, and theranostic capabilities. Special emphasis is placed on dual- and multi-stimuli-responsive nanocarriers, inhalable SRNs for pulmonary delivery, and imaging-guided systems tailored for precision LC therapy. Furthermore, the review provides a critical discussion of the limitations of SRNs, including long-term toxicity, biodegradability concerns, metal ion release, manufacturing scalability, and regulatory hurdles. Despite notable preclinical success, clinical translation remains limited, underscoring the need for biomarker-driven patient selection, standardized toxicity assessment, and GMP-compliant fabrication strategies. Overall, SRNs hold strong potential to advance personalized, effective, and safer lung cancer therapy, but their successful clinical implementation will rely on interdisciplinary collaboration, technological refinement, and translationally oriented research.