Nanocarriers engineering for efficient NSUN2 silencing and immune responsive therapy in metastatic colorectal cancer

Area of Science:

• Nanomedicine and Drug Delivery
• Cancer Biology and Epigenetics
• Immunotherapy

Background:

• Colorectal cancer (CRC) poses a significant global health challenge due to therapeutic resistance and poor drug delivery.
• NSUN2, an RNA methyltransferase, is implicated in CRC progression and immune evasion.
• Targeted delivery of RNA interference (RNAi) agents is crucial for overcoming CRC treatment limitations.

Purpose of the Study:

• To develop a biocompatible, tumor-targeted nanoparticle platform for siRNA delivery.
• To silence the NSUN2 gene in colorectal cancer cells and evaluate its therapeutic potential.
• To assess the efficacy of combination therapy involving NSUN2 silencing and PD-L1 blockade in metastatic CRC models.

Main Methods:

• Engineered poly (lactic acid) (PLA)-based nanoparticles functionalized with RGD and KA26 peptides for tumor targeting and cellular uptake.
• Characterized the physicochemical properties (size, charge, stability) of the PLA-RGD-KA26-siRNA nanocomplexes (PRR).
• Evaluated in vitro NSUN2 knockdown, cancer cell migration inhibition, and cytotoxicity.
• Assessed in vivo therapeutic efficacy in a CT-26 lung metastasis mouse model, including combination therapy with PD-L1 blockade (PRRP).

Main Results:

• PRR nanoparticles demonstrated optimal nanoscale dimensions, positive surface charge, and stability.
• In vitro studies showed enhanced cellular uptake, efficient NSUN2 knockdown, and inhibited cancer cell migration with low normal cell toxicity.
• In vivo administration led to preferential accumulation in metastatic lesions, potent NSUN2 silencing, and significant lung tumor regression.
• PRRP combination therapy synergistically suppressed metastasis, increased T-cell infiltration, reduced proliferation, and enhanced apoptosis without toxicity.

Conclusions:

• The developed tumor-targeted RNA delivery system effectively silences NSUN2, modulating epigenetic pathways in CRC.
• This platform shows significant potential for treating metastatic CRC by combining RNA-based epigenetic regulation with immune checkpoint inhibition.
• The PRRP combination therapy offers a promising strategy for enhancing antitumor immune activity and overcoming therapeutic resistance in metastatic CRC.