Tumor Forcefields

The tumor microenvironment—an amalgamation of signaling molecules, immune cells, fibroblasts, blood vessels, and the extracellular matrix—is seemingly impenetrable. Wei Guo, Hirsch Family President’s Distinguished Professor of Biology, and colleagues from Penn Arts & Sciences, Penn Engineering, and Penn Medicine wanted to understand why.

They found that tumor cells excrete what are known as small extracellular vesicles (sEVs), tiny, fluid-filled sacs that transport materials between cells. These sEVs then act as a “forcefield” of sorts, blocking therapeutics from entering the tumor, results the researchers published in the journal Nature Materials.

“This discovery reveals how tumors create a robust defense system, making it challenging for nanoparticle-based therapeutics to reach and effectively target cancer cells,” Guo says. “By understanding the cellular mechanisms driving these responses, we can potentially develop strategies to disable this defense, allowing therapeutics to penetrate and attack the tumors more efficiently.”

The research builds on a series of previous discoveries from the Guo Lab focused on a type of sEV called exosomes. Those studies had demonstrated that tumor tissues release exosomes carrying inhibitory proteins that block the activity of certain white blood cells that normally kill cancer cells. This laid the groundwork for further investigation, leading the researchers to team up with Michael Mitchell’s laboratory at Penn Engineering and Drew Weissman’s laboratory at the Perelman School of Medicine to figure out how sEVs not only suppress antitumor immune activity but also block nanoparticles.

“Like a bouncer escorting an unruly patron at a bar, the sEVs acted as a decoy, intercepting the nanoparticles and diverting them away from the tumor cells,” says Wenqun Zhong, a research associate in Guo’s lab. “The sEVs come in, pick up the therapeutics, and transport them to the liver, where they are degraded.”

In addition to testing mRNA-loaded lipid nanoparticles, the teams also investigated how other types of nanoparticles and therapeutics interacted with the tumor’s defense mechanism; they found that the sEVs secreted by tumor cells acted as a barrier across many different types of nanoparticles. This was also true for therapeutic antibodies that target proteins highly expressed in tumors. The sEVs similarly served as a decoy, diverting the therapeutic antibodies away from their intended targets on tumor cells, thus reducing their effectiveness.

Using the gene-editing tool CRISPR-Cas9, the researchers knocked out Rab27a, a gene known to play a major role in sEV secretion. They wanted to see whether doing so might allow certain nanoparticles to penetrate the tumor tissue more effectively. As Guo and colleagues expected, the mRNA-loaded lipid nanoparticles entered the tumors and carried out their tumor-inhibiting effects.

The findings from the team—which also included Junhyong Kim, Christopher H. Browne Distinguished Professor of Biology, and Ningqiang Gong, then a Penn postdoc and now an assistant professor at the University of Science and Technology of China—open new possibilities for improving the delivery of these nanoparticle treatments to solid tumors. Moving forward, the researchers say they plan to explore different strategies to disrupt this sEV-based defense system and test the approach in different types of tumors.