Systemic Delivery of Aptamer-Conjugated XBP1 siRNA Nanoparticles for Efficient Suppression of HER2+ Breast Cancer

Abstract

siRNA therapeutics as an emerging class of drug development is successfully coming to clinical utilization. The RNA-based therapy is widely utilized to explore the mechanism and cure a variety of gene-specific diseases. Tumor is an oncogene-driven disease; many genes are related to tumor progression and chemoresistance. Although human epidermal growth factor receptor 2 (HER2)-targeted monoclonal antibody therapy has dramatically improved the survival rate, chemotherapy remains essential to HER2-positive (HER2+) breast cancer patients. Recently, X-box binding protein 1 (XBP1) has been involved in triple-negative breast cancer (TNBC) chemoresistance and progression, but its function in HER2+ breast cancer is poorly explored. Here, we silenced XBP1 expression using RNase-resistant RNA nanoparticles (NPs). Intravenous injection of RNA NPs with HER2-specific aptamers resulted in strong binding to tumors but not to healthy tissues. XBP1 deletion by RNA NPs impaired angiogenesis and inhibited cell proliferation, significantly suppressed breast cancer growth, and promoted the sensitization of chemotherapy in an HER2+ breast cancer mouse model. Overall, these results reveal the function of XBP1 in HER2+ breast cancer development and chemoresistance and imply that targeting XBP1 by RNA NPs may offer an easy and promising strategy for a combination treatment of breast cancer in the future.

Development of Targeted Therapy Therapeutics to Sensitize Triple-Negative Breast Cancer Chemosensitivity Utilizing Bacteriophage phi29 Derived Packaging RNA

“…It should observe that in TNBC, the effect of XBP1 silencing on cell cycle is still no studied. Our previous data showed that XBP1 knock-down in HER2+ breast cancer cell lines results in cell cycle arrest in S phase [4]. Here, we rstly show that XBP1 silencing in TNBC cannot induce cell cycle alternation ( Figure 3c).…”

“…The therapeutic pRNA-EGFRapt-siXBP1 is composed of four strands. Lowercase letters indicate 2'-F modi ed nucleotides, and other sequences are adopted as previously described [4]. The control pRNA-EGFRapt-siScramble is composed of strands with siScramble sequence instead of siXBP1 sequence.…”

“…The size and zeta potential of our NPs were determined by DLS. The Tm value was detected by a SYBR green assay, as previously described [4]. For stability assay, the 2'F modi ed NPs or unmodi ed 3WJ control NPs were exposed to different concentrations RNase A (0, 10, 100 µg/mL), or 10% FBS supplemented DMEM medium at 37 o C, respectively.…”

“…Total RNA was extracted from cultured cells or tumor tissues using a RNeasy mini kit (Qiagen), and reverse-transcription was performed by using HiScript II QRT SuperMix for qPCR (Vazyme Bioteche). Realtime PCR was performed as described previously [4].…”

“…aggregation in vivo, and immune response), which impedes in vivo application [15][16][17]. Recently, we proved that using phi29 bacteriophage-derived pRNA could deliver siRNA with high-e ciency [4]. The RNA nanotechnology was developed in 1998 [18] and has been widely used in cancer therapy [19][20][21].…”