ISTA strategy: A hierarchical nanosystem empowers sequential senotherapy in lung cancer

Senotherapy, which targets senescent cells, offers a promising avenue for cancer treatment but is fundamentally constrained in solid tumors by scarce senescent targets and suboptimal senolytic agents. Inspired by the identification of senescent cells in patient-derived lung adenocarcinoma (LUAD) specimens and our previously reported full- active pharmaceutical ingredient (API) nanodrug (FAND) concept, we report an in situ therapeutic target augmentation (ISTA)-enabled hierarchical dual-FAND strategy for precise and sequential senotherapy. Specifically, we developed two distinct FANDs: a senescence-inducing FAND (Si-FAND) that drives cancer cells into senescence, thereby expanding senescent targets in situ, and a senescence-eliminating FAND (Se-FAND) that clears senescent lung cancer cells. Integrated transcriptomic and proteomic analyses revealed metabolic and translational reprogramming. Collectively, this ISTA-based sequential senotherapy strategy provides a safe, efficient, and clinically relevant approach for senescence-targeted therapy in lung cancer and related diseases.