A tumor microenvironment-responsive polymeric micelle co-delivering alpelisib and cobomarsen suppresses PIK3CA-mutated HR + breast cancer progression by simultaneously blocking PI3K signaling and MDSC-derived exosomal miR-155-5p/SIRT1 axis-mediated epithelial-mesenchymal transition, offering a promising nanotherapeutic intervention for HR + breast cancer. Here, PIK3CA is linked to breast carcinoma.