Utilizing endosomal capture for tumor therapy via membrane-lytic mechanism-based Pickering emulsion

Nanocarriers are easily captured by endosomes, where the abundant hydrolases inevitably destroy the nanocarriers and the drugs they carry, ultimately resulting in a compromised or lost therapeutic efficacy. Herein, we report a membrane-lytic mechanism-based Pickering emulsion that can in turn utilize this seemingly unfavorable endosomal capture behavior for tumor therapy. This Pickering emulsion is constructed as an oil-in-water (O/W) emulsion stabilized by the hybrid nanoparticles (HNPs) composed of two molecules with opposite charges, cetyl trimethylamine bromide (CTAB) and linoleic acid (LA), through electrostatic interaction (defined as [email protected]). After [email protected] enters the lysosomes through macropinocytosis-mediated endocytosis, LA can be protonated in response to the acidic stimulus, and causing the swelling or disintegration of HNPs due to the disrupted electrostatic interaction. The released CTAB holds strong membrane-lytic activity and can directly damage the lysosomal membranes. Under the acidic condition and the participation of excessive iron ions (II) in lysosomes, LA induces lipid peroxidation and the resulting lipid peroxides (LPO) will oxidize the lysosomal membranes, collectively causing the leakage of lysosome membranes and the release of contents into cytoplasm. Subsequently, the diffused CTAB and LPO will continue to attack the mitochondrial membranes and cell membranes, resulting in the death of different types of tumor cells both in vitro and in vivo due to membrane damage. This Pickering emulsion with membrane-lytic ability represents a potential self-anticancer nanocarrier.