Engineered lipid hybrid nanoparticles for targeted delivery of SH2 superbinder and breast cancer therapy.

SH2 Superbinder (SH2S) is an engineered polypeptide tool derived from the SH2 domain. It exhibits significantly enhanced binding capacity for tyrosine-phosphorylated proteins to treat various cancers. However, its clinical application is limited by poor serum stability and insufficient tumor targeting. To solve these problems, engineered SH2S-loaded Lipid Hybrid Nanoparticles (SLHN) was developed by using cationic polymer poly (β-amino ester), lipids and cholesterol via a modified microfluidic technology. SLHN efficiently delivers the SH2S into tumor cells via membrane fusion and clathrin-mediated endocytosis. Inside cells, it replaces natural proteins containing the SH2 domain, then inducing apoptosis and inhibiting growth in tumor cells by blocking the phosphorylation of AKT, ERK and STAT3. Furthermore, SLHN modified with cRGD peptide (SLHN-R) exhibits improved tumor targeting capabilities and and the ability to modulate the tumor microenvironment (promoting CD8+ T cell infiltration and driving M1 macrophage polarization), allowing for efficient breast cancer treatment at lower dosage and with milder adverse effects. Combination of SLHN-R and anti-PD-L1 antibody achieved a better tumor suppression effect. In summary, SLHN demonstrates favorable therapeutic effects against breast cancer both in vitro and in vivo. Particularly, when modified by cRGD, it further enhances its efficacy through specific targeting. This modification enriches the application of lipid-based systems in the delivery of anticancer proteins.