Anti-Pan-Rspo Chimeric Protein-Conjugated Albumin Nanoparticle Provides Promising Opportunities in Cancer Targeted Therapy

Rspos (R-spondins) belong to a family of secreted proteins that causes various cancers via interacting the corresponding receptors. However, targeted therapeutic approaches against Rspos are largely lacking. In this study, a chimeric protein Rspo-targeting anticancer chimeric protein (RTAC) is originally designed, engineered, and characterized. RTAC shows satisfactory anticancer effects through inhibition of pan-Rspo-mediated Wnt/& beta;-catenin signaling activation both in vitro and in vivo. Furthermore, a conceptually novel antitumor strategy distinct from traditional drug delivery systems that release drugs inside tumor cells is proposed. A special firewall nano-system is designed to enrich on tumor cell surface and cover the plasma membrane, rather than undergoing endocytosis, to block oncogenic Rspos from binding to receptors. Cyclic RGD (Arg-Gly-Asp) peptide-linked globular cluster serum albumin nanoparticles (SANP) are integrated as a vehicle for conjugating RTAC (SANP-RTAC/RGD) for tumor tissue targeting. These nanoparticles can adhere to the tumor cell surface and enable RTAC to locally capture free Rspos with high spatial efficiency and selectivity to antagonize cancer progression. Therefore, this approach offers a new nanomedical anticancer route and obtains the dual-targeting capability for effective tumor clearance and low potential toxicity. This study presents a proof-of-concept for anti-pan-Rspo therapy and a nanoparticle-integrated paradigm for targeted cancer treatment.

Automated summary

In this study, a chimeric protein RTAC was designed to target Rspos and showed satisfactory anticancer effects by inhibiting the Wnt/β-catenin signaling pathway. A novel antitumor strategy was proposed, in which a special firewall nano-system was designed to prevent oncogenic Rspos from binding to receptors on the tumor cell surface. The integration of RTAC with cyclic RGD peptide-linked globular cluster serum albumin nanoparticles enabled targeted delivery and efficient capture of free Rspos, resulting in effective tumor clearance and low potential toxicity.