Eliminating blood oncogenic exosomes into the small intestine with aptamer-functionalized nanoparticles

Abstract

There are disease-causing biohazards in the blood that cannot be treated with modern medicines. Here we show that an intelligently designed safe biomaterial can precisely identify, tow and dump a targeted biohazard from the blood into the small intestine. Positively charged mesoporous silica nanoparticles (MSNs) functionalized with EGFR-targeting aptamers (MSN-AP) specifically recognize and bind blood-borne negatively charged oncogenic exosomes (A-Exo), and tow A-Exo across hepatobiliary layers and Oddi’s sphincter into the small intestine. MSN-AP specifically distinguish and bind A-Exo from interfering exosomes in cell culture and rat and patient blood to form MSN-AP and A-Exo conjugates (MSN-Exo) that transverse hepatocytes, cholangiocytes, and endothelial monolayers via endocytosis and exocytosis mechanisms, although Kupffer cells have been shown to engulf some MSN-Exo. Blood MSN-AP significantly decreased circulating A-Exo levels, sequentially increased intestinal A-Exo and attenuated A-Exo-induced lung metastasis in mice. This study opens an innovative avenue to relocate blood-borne life-threatening biohazards to the intestine.

Tumor microenvironment complexity and therapeutic implications at a glance

“…Nanoparticle-A-Exo conjugates can cross hepatobiliary layers and Oddi's sphincter into the small intestine, as validated by significant drop in circulatory A-exo, higher accumulation in the intestine and decreased lung metastasis in mice ( Fig. 5) [188].…”

“…Importantly, cancer growth and in particular, metastatic expansion can be significantly reduced through targeting strategies to block and eliminate tumorderived exosomes [187,188] and/or aggressive CTCs [152,154] from the circulation of cancer patients, as discussed in the earlier sections. In the same way, cfDNA, apoptotic bodies, and exosomes can be used as noninvasive biomarkers for early detection of cancer cells as well as predicting therapy success/relapse.…”

“…Moreover, cfDNA is now recognized as a biomarker of absolute novelty in cancer diagnosis. A substantial number of strategies for breast cancer detection by cfDNA exist, including cfDNA concentration-as the initial quantitative detection method for breast cancer-cfDNA integrity, microsatellite [188] alteration, gene mutations, and DNA methylation, among others [215]. What's more, recently, a machinelearning model that uses the fragmentation pattern of cfDNA across the genome is shown to be capable of revealing tissue-of-origin of seven different cancers at detection sensitivity of 57% to more than 99% with 98% specificity.…”

Extracellular Vesicles in the Development of Cancer Therapeutics

“…These findings support the strategy to suppress cancer metastasis via inhibiting the pro-metastatic functions of cancer-derived sEVs using antibodies against their surface proteins. In addition, an innovative design of aptamer-functionalized nanoparticles was shown to eliminate blood oncogenic sEVs into the small intestine, and attenuate oncogenic sEV-induced lung metastasis in mice [ 103 ]. This technology utilized positively charged mesoporous silica nanoparticles equipped with Epidermal Growth Factor Receptor (EGFR)-targeting aptamers specifically recognizing and binding the negatively charged oncogenic sEVs and towing them from blood to bile duct for elimination.…”

Nucleic Acid Aptamers for Molecular Diagnostics and Therapeutics: Advances and Perspectives

“…Clinical trials have shown that the human body can tolerate micromolar levels of oligonucleotides and deeper penetration of aptamers into the tumor core compared to antibodies [15] . Using positively charged nanoparticles that were functionalized with EGFR‐targeting aptamers, the Jia group reported a study to eliminate blood oncogenic exosomes into the small intestine [16] . As the first large‐scale application of aptamer technology for clinical diagnosis, Tan et al.…”