Piperine (PIP), a compound found inPiper longum, has shown promise as a potential chemotherapeutic agent for breast cancer. However, its inherent toxicity has limited its application. To overcome this challenge, researchers have developed PIP@MIL-100(Fe), an organic metal–organic framework (MOF) that encapsulates PIP for breast cancer treatment. Nanotechnology offers further treatment options, including the modification of nanostructures with macrophage membranes (MM) to enhance the evasion of the immune system. In this study, the researchers aimed to evaluate the potential of MM-coated MOFs encapsulated with PIP for breast cancer treatment. They successfully synthesized MM@PIP@MIL-100(Fe) through impregnation synthesis. The presence of MM coating on the MOF surface was confirmed through SDS-PAGE analysis, which revealed distinct protein bands. Transmission electron microscopy (TEM) images demonstrated the existence of a PIP@MIL-100(Fe) core with a diameter of around 50 nm, surrounded by an outer lipid bilayer layer measuring approximately 10 nm in thickness. Furthermore, the researchers evaluated the cytotoxicity indices of the nanoparticles against various breast cancer cell lines, including MCF-7, BT-549, SKBR-3, and MDA. The results demonstrated that the MOFs exhibited between 4 and 17 times higher cytotoxicity (IC50) in all four cell lines compared to free PIP (IC50= 193.67 ± 0.30 µM). These findings suggest that MM@PIP@MIL-100(Fe) holds potential as an effective treatment for breast cancer. The study’s outcomes highlight the potential of utilizing MM-coated MOFs encapsulated with PIP as an innovative approach for breast cancer therapy, offering improved cytotoxicity compared to free PIP alone. Further research and development are warranted to explore the clinical translation and optimize the efficacy and safety of this treatment strategy.