An acid degradable, lactate oxidizing nanoparticle formulation for non-small cell lung cancer virotherapy

Approved targeted therapies for non-small cell lung cancer (NSCLC) though initially effective, often eventually fail due to emergence of drug resistance. This evolution is frequently associated with specific driver mutations and greater reliance on aerobic glycolysis, which can increase lactate production in the tumor microenvironment (TME). Meanwhile, oncolytic virotherapy has been approved since 2015, however systemic administration remains particularly challenging and viral delivery for the genome-editing tool of the clustered regularly interspaced short palindromic repeats (CRISPR) system has continued to elicit major concerns due to off targeting. Nevertheless, sophisticated yet robust formulation of viral therapeutics stands to revolutionize their specificity. Notably, physico-chemical properties such as acidosis can regulate viral release and additionally promotes viral transduction. Herein, we report exploitation of NSCLC tumor-secreted lactate in designing an acid-degradable nanoparticle containing the acyclic acetal component of oxidized hyaluronic acid (HA) for the release of virus. The virus, lactate oxidase (LOX), and hexanoamide are conjugated with aldehyde-HA through reductive amination. LOX catalyzes the oxidation of lactate (pKa = 3.9) to pyruvate (pKa = 2.5), modulating a localized lowering of pH and triggering destabilization of the acyclic component-based nanoparticles. The lower pH can facilitate virus internalization into cells due to pH-sensitive proteases of viral capsid. Site-specific delivery is proven by viral transduction in the NSCLC tumor-secreted lactate microenvironment, offering an avenue for improving general or drug-resistant NSCLC treatment outcomes.