Nanomedicine for lymphangioleiomyomatosis: toward targeted and durable anti-fibrotic therapy

Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease primarily affecting women, driven by TSC1 or TSC2 mutations that lead to constitutive mTORC1 activation and progressive respiratory failure. While rapamycin remains the only approved treatment, it is disease-stabilizing rather than disease-reversing. Recent studies demonstrate that lung-targeted lipid nanoparticles delivering functional TSC2 mRNA can restore tumor suppressor activity, inhibit mTORC1 signaling, and reduce cystic lung damage in preclinical models, offering a potential disease-modifying approach. Effective nanomedicine delivery to LAM lungs faces significant barriers, including mucus entrapment, altered airflow, and fibrotic remodeling, necessitating mucus-penetrating formulations for uniform deposition. Advances in nanoparticle-based anti-fibrotic therapy from related conditions such as liver fibrosis support the translational promise of this approach. Clinical trials are urgently needed to optimize design, evaluate safety, and assess efficacy in patients with LAM, with the goal of achieving targeted, durable, and personalized therapy.