Arginine Polymer-Based Nanoplatform Facilitates Oral Co-Delivery of Antibody/Antigen for Robust Oral Immunotherapy in Orthotopic Colon Cancer.

Immune checkpoint blockade and therapeutic cancer vaccines have transformed cancer treatment, yet their clinical application in colorectal cancer remains constrained by the lack of efficient oral delivery strategies for biomacromolecules such as antibodies and protein antigens. Here, we report a smart oral immunotherapy strategy that enables the codelivery of programmed death-ligand 1 antibody (anti-PD-L1) and ovalbumin (OVA) antigen for localized colorectal cancer treatment through an arginine-based polymeric nanoplatform. A biosafe cationic arginine-derived polymer (2A6S) was rationally engineered to electrostatically load both antibody and antigen cargos, while an enteric polymer coating (EudragitL100) protected the nanocomplexes from gastric degradation and ensured intestinal release. This dual-protective oral platform (EAPO NPs) achieved efficient colon lesion delivery and significantly enhanced local antitumor immune activation in an orthotopic MC38-OVA colorectal tumor model. Encouragingly, oral administration of EAPO NPs induced 53.34% tumor inhibition using only twice the antibody/antigen dosage compared with systemic injection, while substantially reducing potential systemic immunotoxicity. By integrating immune checkpoint blockade with antigen-specific immune priming through a single oral nanoplatform, this work establishes a simple, safe, and effective strategy for localized intestinal immunotherapy, which could be applicable to colorectal cancer and other colon-associated diseases.