AI Article Synopsis

  • Immunotherapy is becoming a leading approach for treating cancer, particularly with the activation of the cGAS-STING pathway that helps direct tumor-associated macrophages (TAMs) to fight tumors more effectively.
  • Researchers have developed a new type of manganese porphyrins called photo-STING agonists (PSAs) and packaged them into nanoparticles that target tumors and TAMs, enhancing the delivery of manganese while reducing toxicity.
  • These PSAs not only improve manganese delivery but also trigger the release of reactive oxygen species when exposed to light, stimulating the immune response that leads to better tumor eradication through the activation of dendritic cells and T lymphocytes.

Article Abstract

Immunotherapy has emerged as a highly effective therapeutic strategy for cancer treatment. Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon gene (STING) pathway activation facilitates tumor-associated macrophage (TAM) polarization toward M1 phenotype, and Mn are effective agents for this pathway activation. However, the high in vivo degradation rate and toxicity of Mn hamper clinical application of immunotherapy. Here, this work has newly synthesized and screened manganese porphyrins for Mn transport, referred to as photo-STING agonists (PSAs), and further encapsulate them into core-shell nanoparticles named Rm@PP-GA with dual specificity for tumor tissue and TAMs. Not only do PSAs achieve higher Mn delivery efficiency compared to Mn, but they also generate reactive oxygen species under light exposure, promoting mitochondrial DNA release for cGAS-STING pathway activation. In Rm@PP-GA, globin and red blood cell membranes (Rm) are used for erythrocyte efferocytosis-mimicking delivery. Rm can effectively prolong the in vivo circulation period while globin enables PSAs to be taken up by TAMs via CD163 receptors. After Rm rupture mediated by perfluorohexane in nanoparticles under ultrasonication, drugs are specifically released for TAM repolarization. Further, dendritic cells mature, as well as T lymphocyte infiltrate, both of which favor tumor eradication. Therefore, cancer immunotherapy is optimized by novel PSAs delivered by erythrocyte efferocytosis-mimicking delivery pattern.

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Source
http://dx.doi.org/10.1002/adma.202410937DOI Listing

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