Therapeutic Peptide-Programmed Liquid-Crystalline Topology Switching for pH-Gated Postoperative Cancer Immunotherapy

Stimuli-responsive depots for postoperative cancer therapy often treat therapeutic payloads as passive cargo, resulting in premature leakage and limited on-demand activation. Herein, we report a therapeutic peptide-programmed liquid-crystalline depot in which the Vpr-derived antitumor peptide (VDAP) functions simultaneously as an immunotherapeutic effector and a supramolecular topology regulator. At physiological pH, cationic α-helical VDAP was electrostatically anchored by oleic acid-containing lipid domains, reinforcing a compact inverse hexagonal (H_II) topology associated with reduced peptide diffusion. In the acidic postoperative tumor microenvironment, protonation of oleic acid could disrupt anionic anchoring, whereas histidine protonation within VDAP amplified intrachannel electrostatic repulsion. This cooperative peptide-lipid charge reprogramming could drive graded liquid-crystalline topology remodeling from a diffusion-restrictive H_II organization to a more interconnected bicontinuous cubic Im3̄m network, consistent with increased pH-responsive peptide release. In an orthotopic incomplete-resection breast tumor model, the depot induced immunogenic tumor destruction, enhanced damage-associated molecular pattern release, promoted dendritic cell maturation and CD8⁺ T cell infiltration, and reshaped the immunosuppressive surgical bed. These results demonstrate that electrostatic-topology-gated VDAP-enabled supramolecular topology switching provides effective adaptive local cancer immunotherapy, effectively suppressing postoperative tumor recurrence and attenuating pulmonary metastasis.