Fullerene-based nanocomplex assists pulmonary delivery of siRNA for treating metastatic lung cancer

Non-hepatic delivery of small interfering RNA (siRNA) remains a challenge for the development of RNA interference (RNAi)-based therapeutics. Inhalation is a straightforward and highly efficient route of delivering drugs to airways and pulmonary parenchyma, thus offering an opportunity for the novel paradigm of siRNA to treat lung diseases. Herein, we designed a fullerene-based nanocomplex to achieve the pulmonary delivery of siRNA via inhalation. The obtained nanocomplex protects encapsulated siRNA against nucleases degradation, improves the cellular uptake and gene knockdown efficiency, and prolongs the pulmonary retention of siRNA after inhalation. Through the package of programmed death-ligand 1 (PD-L1) siRNA, this nanocomplex significantly inhibits the progression of metastatic lung cancer without obvious adverse events and toxicity in a mouse model. This fullerene-based nanocomplex could open up the possibility of siRNA for treating a diverse range of pulmonary diseases.