Inhalable mucus-penetrating and senescence-targeted nanoliposomes reverse senescence to overcome chemoresistance for enhanced lung cancer therapy.

Abstract

Lung cancer therapy is severely hindered by the pulmonary mucus barrier and chemotherapy resistance driven by therapy-induced senescence (TIS) following DNA-damaging agents. Herein, we report an inhalable, mucus-penetrating nanoliposomes (DR@DPPC-Apt) engineered by incorporating an L1 cell adhesion molecule (L1CAM)-targeting cholesterol-modified aptamer into dipalmitoyl phosphatidylcholine (DPPC)-based nanoliposomes co-encapsulating rapamycin and doxorubicin. Upon noninvasive inhalation, the nanoliposomes leverage compositional similarity to efficiently traverse the mucus barrier and actively target senescent lung cancer cells via aptamer-mediated recognition of overexpressed L1CAM, achieving enhanced cellular uptake and selective drug accumulation in tumor sites. Intratumorally, rapamycin potently inhibits the mammalian target of rapamycin (mTOR) pathway to reverse the senescent phenotype, which in turn enhances drug retention, hyperactivates autophagy, and blocks senescence propagation, thereby resensitizing cancer cells to chemotherapy and overcoming acquired resistance. In a chemoresistant lung cancer mouse model, inhalation of DR@DPPC-Apt significantly suppresses tumor growth without appreciable systemic toxicity. This strategy establishes a highly effective therapeutic paradigm for chemoresistant lung cancer by integrating senescence-targeted delivery with pharmacological senescence reversal, thereby offering a promising clinically translatable approach for enhanced lung cancer therapy.