Aptamer-conjugated dual-loaded liposomes exhibit synergistic effects in hepatic tumor treatment

Norcantharidin (NCTD) is commonly used for treating primary liver cancer and is predominantly administered in tablet and injection forms. Despite its potent anti-hepatic tumor effects, it is associated with numerous side effects. Paeonol (Pae), a main component of the traditional Chinese medicine Mudanpi, exhibits various biological activities and anti-tumour effects with low toxicity. However, the clinical application of Pae is hindered by its poor water solubility and insufficient anti-tumour efficacy. In this study, we successfully developed a dual-drug simultaneous delivery smart nanodrug delivery system (Apt-ss-Pae-Lip+ Apt-ss-NCTD-Lip) characterised by active targeting and responsive release. This system employs liposomes with redox-sensitive environmental responsiveness as carriers, functionalising and modifying their surfaces with aptamers and encapsulating either norcantharidin or paeonol. Both Apt-ss-Pae-Lip and Apt-ss-NCTD-Lip served as carriers.Apt-ss-NCTD-Lip and Aptss-Pae-Lip can specifically respond to reducing environments and exhibit significant synergistic anti-tumour effects. NCTD and Pae influence the p53 and reactive oxygen species(ROS) signalling pathways, respectively, with mutual activation of these pathways inducing apoptosis, which is crucial for synergism. Activation of the mitochondrial apoptotic pathway is one of the mechanisms through which these effects are exerted. This dual- drug synchronous intelligent delivery system demonstrated enhanced tissue targeting of HepG2 hepatocellular carcinoma, enabling rapid drug release at the target site and improving therapeutic efficacy. Simultaneously, they reduce drug toxicity in normal tissues and organs, thereby enhancing safety. This environmentally responsive, active, and targeted nano-delivery system presents significant developmental advantages.