Professor Zhaohui Tang and Associate Professor Zhilin Liu from Professor Xuesi Chen’s group at the Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, developed in-situ ultrasound-responsive antigen nanocatchers (S-nanocatchers), achieving precise antiaging tumor capture and control. vaccines. This system solves the key problems of traditional antigen-binding nanocarriers, such as their tendency to non-specifically bind to serum proteins during systemic circulation and their low antigen capture efficiency, providing a new strategy for personalized tumor immunotherapy. The article was published as an open access research article at CCS Chemistrythe flagship journal of the Chinese Chemical Society.
Background information:
The high heterogeneity of tumor antigens in cancer patients is a key limiting factor for improving the efficacy of tumor vaccines, with significant differences in antigen characteristics between different patients and even different lesions in the same patient. In situ tumor vaccine strategies, using endogenous antigens directly in the tumor microenvironment, eliminate the need for complex antigen separation procedures, effectively overcoming this challenge of heterogeneity. Currently used antigen delivery methods such as phototherapy and radiation therapy have limitations, including shallow tissue penetration and potential damage to normal tissues. Ultrasound technology, with its deep penetration and high biocompatibility, has become an ideal stimulus for in situ vaccine development. However, ultrasound-mediated antigen delivery alone faces challenges such as poor antigen stability and insufficient dendritic cell (DC) presentation, limiting immune activation. Achieving efficient acquisition and accurate capture of antigens in situ has become a major breakthrough in improving the efficacy of in situ vaccines.
Highlights of this article:
This study designed sonicated responsive antigen catchers, S-nanocatchers, with polyglutamic acid (PLG) as the main chain, attached to a thioether-containing antigen capture group (S-ACG) and the sonicated factor pyrophyllophetate α (PPA). After self-assembly, the hydrophobic S-ACG and PPA are encapsulated in the nanoparticle core, avoiding non-specific interactions with serum proteins during systemic circulation. When treated with ultrasound, reactive oxygen species (ROS) produced by PPA not only induce immunogenic death (ICD) of cancer cells to release antigens, but also oxidize the thioether to hydrophilic sulfones or sulfoxides, exposing the antigen-capturing group on the effective surface of the nanoparticle. molecules, peptides and tumor antigens.
The control group (C-nanocatchers) replaced its thioether with a carbon chain and showed no significant antigen-binding capacity regardless of whether it was sonicated, confirming the sulfur oxidation-dependent switching mechanism. This system efficiently activates dendritic cell (DC) maturation and migration. In combination with the TLR7/8 agonist IMDQ, it achieved a primary tumor inhibition rate of 93.4% and a distant tumor regression rate of 60% in a B16F10 melanoma mouse model, without significant systemic toxicity. By enhancing the infiltration of CD8-positive T cells and the release of cytokines such as IFN-γ and TNF-α, it remodels the antitumor immune microenvironment, providing a universal and precise personalized immunotherapy platform.
Summary and Outlook:
This study combines ultrasound-guided antigen capture with in situ vaccine synthesis, achieving precise spatiotemporal capture of tumor antigens via a thioether oxidation “smart switch” mechanism, effectively solving the non-specific binding problem of traditional nanocarriers. Ultrasound-responsive antigen catchers (S-nanocatchers) can not only effectively induce local immune responses, but also activate systemic antitumor immunity through combination with adjuvants, providing a novel solution to address tumor heterogeneity and distant metastasis.
