Carbonic Anhydrase Targeting Polymer with Enhanced Intracellular Protein Delivery and Tumor Penetration for Cancer Therapy.

Protein-based therapeutics demonstrate significant potential for cancer treatment, but their clinical application is often limited by poor tumor penetration, inefficient cellular uptake, and diminished activity in the acidic tumor microenvironment (TME). To overcome these challenges, we developed a cationic polymer modified with benzenesulfonamide groups as a protein delivery vehicle. This modification enhances protein binding through hydrophobic and hydrogen-bonding interactions, promotes cellular uptake and endosomal escape, and inhibits carbonic anhydrase IX in cancer cells to neutralize the acidic TME and suppress tumor growth. Furthermore, the polymer targets the Golgi apparatus, enabling an intercellular transfer pathway that improves the deep tumor penetration. In B16 melanoma-bearing mice, the engineered polymer facilitated efficient delivery of α-chymotrypsin to tumor sites, resulting in a significant inhibition of tumor growth. This work presents a versatile protein delivery strategy that combines TME modulation with organelle-specific trafficking for enhanced tumor targeting.