Peptide-lipid nanoparticle-mediated delivery of p53-circRNA synergizes with everolimus for dual suppression of PI3K/AKT/mTOR pathway

The PI3K/AKT/mTOR (PAM) pathway is aberrantly activated in about 50% of human cancers, serving as a critical therapeutic target. However, the efficacy of PAM inhibitors is often compromised by intrinsic resistance, especially in p53-deficient non-small cell lung cancer (NSCLC). Here, we develop peptide-lipid nanoparticles encapsulating p53-encoding circular RNA (p53-CircRNA) with 96% efficiency, outperforming SM-102 in delivery and restoring p53 to 2.5-fold over controls. Combined with half-dose everolimus, this system induced near-complete tumor regression (98% inhibition) in orthotopic NSCLC models. Mechanistically, p53-CircRNA restore PTEN and suppress PI3K/AKT feedback, while everolimus directly inhibit mTOR, establishing coordinated PAM blockade. Furthermore, p53-CircRNA reverse everolimus-induced pro-survival autophagy, reducing ATG7 and LC3B-II levels by 80%, and redirect the response toward apoptotic cell death. This strategy not only enhance antitumor efficacy but also significantly mitigate everolimus-related hepatotoxicity. Our work establishes peptide-lipid–based p53-CircRNA delivery as a clinically viable approach to overcome PAM inhibitor resistance in p53-deficient cancers.