Cryo-Electron Tomography-Guided Nanoparticle Delivery Framework for Targeted Intratumoral siRNA Transfection in Triple-Negative Breast Carcinoma Microenvironments
Keywords:
triple-negative breast carcinoma, siRNA nanoparticle delivery, cryo-electron tomography, lipid-polymer hybrid nanoparticles, tumor microenvironment, PLK1/STAT3 oncogenic silencing, endosomal escape optimization, TNBC organoid models, precision oncology therapeuticsAbstract
Triple-negative breast carcinoma (TNBC) remains refractory to conventional systemic therapies due to the absence of targetable hormone receptors and the immunosuppressive complexity of its tumor microenvironment (TME). This study presents a cryo-electron tomography (cryo-ET)-guided lipid-polymer hybrid nanoparticle (LPHN) delivery framework optimized for intratumoral small interfering RNA (siRNA) transfection targeting PLK1 and STAT3 oncogenic axes. Methodological optimization encompassed iterative cryogenic structural mapping, surface ligand conjugation profiling, and endosomal escape efficiency quantification across ex vivo TNBC organoid models. Results demonstrated a 78.4% transfection efficiency with a concomitant 61.2% reduction in target gene expression and markedly attenuated tumor spheroid proliferation indices. Cytotoxicity profiling confirmed selective oncotoxicity with preserved non-malignant stromal cell viability. These findings establish a structurally validated, reproducible nanoparticulate RNA delivery architecture with translational relevance for precision oncology therapeutics.
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