A groundbreaking study published in Advanced Science has introduced a promising nanotherapy that precisely targets one of the most challenging drivers of metastatic prostate cancer. The therapy takes aim at HoxB13, a transcription factor identified as a key player in the disease’s progression—yet long considered “undruggable” due to its structure and inaccessibility to traditional small-molecule drugs. Transcription factors like HoxB13 regulate essential cancer signaling pathways, but until now, efforts to inhibit them have been hampered by the limitations of existing drug technologies.

To overcome this challenge, researchers developed an innovative strategy called Selective Cell in ORgan Targeting, or SCORT. This approach uses engineered lipid nanoparticles (LNPs) to deliver RNA-based therapeutics directly to metastatic cancer cells within the body. Specifically, the SCORT system transports messenger RNA encoding Cas13d (an RNA-targeting enzyme known as CasRx) along with a specially designed guide RNA (gRNA) that directs CasRx to the HoxB13 transcript. The result is a targeted knockdown of HoxB13 expression in metastatic prostate cancer cells.

The design of these SCORT LNPs was key to their success. The researchers incorporated an ionizable lipid called FTT5, which facilitates efficient RNA delivery in living organisms. To ensure the nanoparticles reach cancer cells rather than healthy tissue, they decorated the surface of the LNPs with an E3 aptamer that binds transferrin receptor 1 (TfR1), a protein overexpressed in many metastatic cancer cells, including castration-resistant prostate cancer (CRPC). Additionally, they fine-tuned the composition of the LNPs—especially the balance of PEG-lipids—to create a particle size and surface profile that promotes selective uptake by cancer cells over normal liver cells.

Laboratory studies confirmed that HoxB13 is significantly overexpressed in metastatic CRPC compared to early-stage prostate cancer and normal prostate tissue. Using a guide RNA called HoxB13-4, the researchers achieved nearly complete knockdown of HoxB13 in CRPC cell lines. This suppression effectively blocked the cells’ growth and invasiveness without harming normal liver cells. RNA sequencing further revealed the intervention was highly specific, with minimal off-target effects.

Animal studies strengthened the case for SCORT-CasRx-pre-gHoxB13 as a viable treatment. In mouse models with liver metastases from CRPC, the nanoparticles accumulated primarily in cancerous tissues, sparing healthy organs such as the heart, lungs, kidneys, and surrounding liver tissue. Fluorescent tracking and immunohistochemical analyses confirmed that the therapeutic RNA payload was successfully delivered and expressed in tumor cells. When administered repeatedly, the treatment significantly slowed the spread of metastases and extended survival in both androgen receptor-positive and androgen receptor-negative prostate cancer models.

Importantly, the treatment was well-tolerated. Normal mice receiving biweekly doses for over six weeks showed no signs of toxicity based on body weight, organ function, blood chemistry, or inflammatory markers. This favorable safety profile is credited to several factors: the biocompatibility of the nanomaterials, the RNA-targeting (rather than DNA-altering) nature of CasRx, its origin from a non-pathogenic microbe (which reduces immune complications), and the fact that HoxB13 is not widely expressed in healthy adult tissues.

Mechanistically, the therapy inhibited tumor growth by curbing cell proliferation, reducing the formation of blood vessels that feed tumors, and triggering cancer cell death. Transcriptome analysis revealed that SCORT-CasRx-pre-gHoxB13 reprogrammed gene expression in the tumors, downregulating oncogenic pathways and activating tumor-suppressive ones. It also disrupted the function of Snail, a transcription factor involved in cancer metastasis, further impairing the tumor’s ability to survive and spread.

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