Zwitterionic peptide dendrimer-based nanocarriers with enhanced stability and biocompatibility for cancer therapy.

Autophagy is a cellular self-degradation process that plays a dual role in cancer. Its mild activation can promote tumor survival, while its excessive activation may lead to autophagy-related cell death. Therefore, synergistic treatment of chemotherapeutic agents and autophagy inducers could be a potential strategy to improve therapeutic outcomes. In this study, a zwitterionic peptide dendrimer was designed to conjugate chemotherapeutics, while autophagy inducer STF-62247 was co-loaded into the zwitterionic vehicles to form zwitterionic peptide dendrimers-based nanoparticles (ZPNs). The zwitterionic peptide dendrimer-based vehicles integrate the advantages of peptide dendrimers and zwitterionic surface properties, enabling self-assembly into a stable nanoscale co-delivery system. The physicochemical characteristics of ZPNs, including size, morphology, surface charge, and stability were studied by dynamic light scattering (DLS), transmission electron microscopy (TEM), a hemolysis assay, and protein adsorption assays. The activated autophagy was observed by TEM and Western Blot (WB) tests, which revealed enhanced autophagy in treated tumor cells. In vivo studies in 4T1 tumor-bearing mice were performed to evaluate both antitumor activity and systemic safety, accompanied by histological and hematological analyses. The results showed that ZPNs@STF achieved tumor inhibition comparable to doxorubicin (DOX) while reducing systemic toxicity, suggesting that zwitterionic peptide dendrimers as a promising and safe platform for combination chemotherapy.