Inhalable nanoliposomes target senescence and overcome chemoresistance in mouse lung cancer
The formulation co-delivers rapamycin and doxorubicin across the mucus barrier to inhibit mTOR and suppress tumor growth without evident systemic toxicity.
In a chemoresistant lung cancer mouse model, researchers tested an inhalable nanoliposome system engineered to traverse the pulmonary mucus barrier and target senescent cancer cells. The lipid nanoparticles incorporated an aptamer targeting L1 cell adhesion molecule (L1CAM) to co-deliver rapamycin and doxorubicin directly to tumor sites. Upon inhalation, the formulation selectively accumulated in senescent lung cancer cells overexpressing L1CAM. Inside tumors, rapamycin inhibited the mTOR pathway, which reversed the senescent phenotype, hyperactivated autophagy, blocked senescence propagation, and enhanced drug retention. This molecular shift resensitized the cancer cells to chemotherapy. Inhalation of the nanoliposomes significantly suppressed tumor growth in the mice without causing appreciable systemic toxicity.
Why it matters
Therapy-induced senescence can propagate and drive acquired resistance to DNA-damaging treatments. Targeting and pharmacologically reversing this senescent phenotype via mTOR inhibition provides a way to disrupt senescence-driven pathology directly in diseased tissue.
Caveats
The findings are restricted to a chemoresistant mouse model, and the formulation has not yet been tested in human clinical trials.
- Doxorubicin
- Rapamycin
- Rapamycin + doxorubicin
- Cellular senescence
- Disabled macroautophagy
- Autophagy
- mTOR signalling
- L1cam
- Chemoresistant lung cancer
- Lung cancer
- Mus musculus
The paper
Inhalable mucus-penetrating and senescence-targeted nanoliposomes reverse senescence to overcome chemoresistance for enhanced lung cancer therapy
Man Y, Liu Y, Liu Y et al.
Biomaterials · 23 Sep 2026