PROTAC technology presents promising options for treating various diseases, including cancer. Several PROTAC molecules are currently being tested in clinical trials for metastatic breast cancer and metastatic castration-resistant prostate cancer. Despite this progress, challenges such as poor bioavailability, off-tumor and/or off-target toxicity, and instability in biological environments hinder their therapeutic potential. Enhancing the therapeutic index of PROTACs is crucial, and one promising approach is converting PROTACs into nanomedicines. Cyclin-dependent kinase 9 (CDK9) is a key cell cycle regulator implicated in various cancers. THAL-SNS-032 (THAL), a CDK9 degrader PROTAC, has shown effectiveness in preclinical models, but its clinical translation is limited by on-target off-tumor toxicity. This study aimed to convert THAL into nanomedicines to improve its preclinical profile for breast cancer treatment. To do so, loaded lipid-based nanoparticle formulations (LBNPs) were designed, liposomal formulation (cLIP-THAL), free-cholesterol liposomal formulation (LIP-THAL), and solid-lipid nanoparticles (SLN-THAL). These formulations demonstrated high stability and controlled drug release of THAL, with cLIP-THAL showing the most promising results. Biological assessments on breast cancer cell lines indicated that the nanomedicines were as effective as the free PROTAC in reducing cell viability, with lower toxicity in non-transformed cells. Overall, incorporating THAL-SNS-032 into nanomedicines offers a comprehensive approach with potential benefits in dose optimization, safety, and targeted delivery. These findings support the further development of nanomedicine-based PROTAC therapies for cancer treatment.