We report that HIF2α-CD27 PAMs were consistently more efficacious than both free siRNA and non-targeted PAMs in silencing gene expression and inhibiting their oncogenic functions in glucose metabolism, cell cycle progression, angiogenesis, and cell migration, highlighting the importance of both siRNA encapsulation and molecular targeting, and demonstrating the potential of HIF2α-CD27 PAMs for ccRCC-specific drug delivery. This evidence concerns the gene EPAS1 and nonpapillary renal cell carcinoma.