An Ultrasonic Probe-Fabricated Nanocapsule for Cytomembrane-Anchoring Photodynamic Therapy and <i>In Situ</i> Tumor Vaccine

Lipopolysaccharide (LPS) is recognized as a promising candidate for immunotherapy due to its potent immunogenic properties. However, this strong immunogenicity necessitates precise and protective delivery strategies to ensure safe and effective application. In this study, an ultrasonic probe-fabricated nanocapsule was first developed. Owing to the hydrophobic barrier provided by the system, LPS covalently linked methyl acrylated hyaluronic acid (HAMA-LPS) based surfactant-free emulsion polymerization occurred exclusively at the interface of monomer vesicles, resulting in the formation of a hollow-structured nanocapsule. This structure not only protected the immunogenic LPS from oxidative damage in free radical polymerization but also enabled the in situ loading of the hydrophobic photosensitizer chlorin e6 (Ce6). The prepared nanocapsules achieved a 1.53% loading rate of Ce6 and could effectively generate ROS under laser irradiation and undergo acid/enzyme-responsive release. Following cellular uptake by tumor cells, the nanocapsule underwent degradation mediated by hyaluronidase, leading to the release of LPS-Ce6. Subsequently, LPS-Ce6 anchored onto the tumor cell membrane via hydrophobic interactions and exerted photodynamic therapy upon laser irradiation. This therapeutic strategy elicited a robust immune response. On the one hand, photodynamic therapy compromised cell membrane integrity, thereby promoting the release of damage-associated molecular patterns. More importantly, the membrane-anchored LPS-Ce6 acted as an in situ antitumor vaccine, providing a focal point for monocyte and macrophage recruitment, while inducing macrophage polarization toward the M1 phenotype and stimulating the secretion of various antitumor cytokines. Both <i>in vitro</i> and <i>in vivo</i> experimental results demonstrated that the nanocapsule effectively inhibited tumor growth and generated a significant antitumor immune response.