Targeting lung cancer utilizing smart nanoparticles: Nanomedicine meets tumor stroma

Lung cancer remains a leading cause of global cancer-related mortality. Progress in cancer biology suggests that it is driven by the dynamic crosstalk between malignant cells and the tumor stroma. This stromal microenvironment exhibits unique pathophysiological features, including hypoxia, acidic pH gradients, altered metabolism and reduction/oxidation (redox) balance, leaky vasculature, and dysregulated enzyme activity. These properties not only promote tumor aggressive properties and therapy resistance but also offer actionable targets for nanotechnology-driven interventions. Smart nanoparticles are engineered carriers to exploit such stromal anomalies and target these unique properties of the tumor stroma. Stimuli-responsive designs, such as redox/pH-sensitive nanocarriers, hypoxia-activated prodrug carriers, enzyme-stimuli and vasculature-targeting agents, enable spatially controlled therapy using nanoparticles. Functionalization of nanoparticles using specific responsive covalent linkers (e.g., imine for pH sensitivity), redox-labile motifs (e.g., disulfide), ROS/glutathione (GSH)-reactive groups, enzyme-cleavable peptide sequences, thermoresponsive polymers (e.g., PNIPAM) and modular targeting moieties like RGD, aptamers, small molecules (e.g., folate), and monoclonal antibodies have shown promising results in preclinical studies. In addition, innovations like dual-responsive nanocarriers can synergistically attack stromal and cancer cells to amplify antitumor therapy. This review aims to evaluate recent progress in the tumor targeting utilizing smart nanoparticles. By uniting nanotechnology with stromal biology, this paper explores recent knowledge of lung tumor stroma and its unique targets for targeting by smart nanoparticles.