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Intratumoral immunotherapy is an emerging modality for the treatment of solid tumors. Toll-like receptor (TLR) agonists have shown promise for eliciting immune responses, but systemic administration often results in the development of adverse side effects. Herein, we investigate whether localized delivery of the TLR agonist, resiquimod (R848), via platelet membrane-coated nanoparticles (PNP-R848) elicits antitumor responses. The membrane coating provides a means of enhancing interactions with the tumor microenvironment, thereby maximizing the activity of R848. Intratumoral administration of PNP-R848 strongly enhances local immune activation and leads to complete tumor regression in a colorectal tumor model, while providing protection against repeated tumor re-challenges. Moreover, treatment of an aggressive breast cancer model with intratumoral PNP-R848 delays tumor growth and inhibits lung metastasis. Our findings highlight the promise of locally delivering immunostimulatory payloads using biomimetic nanocarriers, which possess advantages such as enhanced biocompatibility and natural targeting affinities. The immunostimulatory properties of TLR7/8 agonists, such as resiquimod, have been exploited for cancer immunotherapy. Here, the authors design platelet membrane-cloaked nanoparticles for selective intratumoral delivery of resiquimod, resulting in potent anti-tumor immune response in a range of preclinical solid tumors.

Hydrogen sulfide is a highly toxic gas—second only to carbon monoxide as a cause of inhalational deaths. Its mechanism of toxicity is only partially known and no specific therapy exists for sulfide poisoning. We show in several cell types, including human inducible pluripotent stem cell (hiPSC)-derived neurons, that sulfide inhibited complex IV of the mitochondrial respiratory chain and induced apoptosis. Sulfide increased hydroxyl radical production in isolated mouse heart mitochondria and F 2 -isoprostanes in brains and hearts of mice. The vitamin B 12 analog cobinamide reversed the cellular toxicity of sulfide and rescued Drosophila melanogaster and mice from lethal exposures of hydrogen sulfide gas. Cobinamide worked through two distinct mechanisms: direct reversal of complex IV inhibition and neutralization of sulfide-generated reactive oxygen species. We conclude that sulfide produces a high degree of oxidative stress in cells and tissues and that cobinamide has promise as a first specific treatment for sulfide poisoning.

Significance Early signaling events leading to protection in the heart under cardiac injury are poorly understood. We identified one such protein, A kinase interacting protein (AKIP1), as a modulator that responds to oxidative stress; up-regulation of AKIP1 showed protection to ischemic injury through enhanced mitochondrial integrity. We show AKIP1 functions as a molecular scaffold via interaction with mitochondrial apoptosis inducing factor and increases protein kinase A activity. These mitochondrial signaling complexes assembled by AKIP1 alter the physiological response of the heart under ischemic stress. Understanding molecular activity and regulation of AKIP1 could lead to novel therapeutic approaches to limit myocardial injury.