The project addresses the prevalent issue of bacterial infections in orthopedic surgeries involving bone substitutes, aiming to combat antibiotic resistance through innovative approaches. It focuses on using (lipid-)oligonucleotides associated with bone substitutes, primarily calcium phosphates, commonly used in bone regeneration. The research comprises three key axes: -Understanding the interactions between calcium phosphates and (lipid-)oligonucleotides, involving synthetic model sequences to delve into their mechanisms and improve efficacy. -Developing (lipid-)oligonucleotides targeting Gram-positive bacteria, especially coagulase-positive staphylococci and methicillin-resistant Staphylococcus aureus (MRSA). -Combining (lipid-)oligonucleotides with bone substitutes, particularly calcium phosphate cements, to assess their stability, release capabilities, and interactions with the substrate. This interdisciplinary approach aims to create bioactive biomaterials for bone regeneration and provide a unique solution to antibiotic resistance. The project also opens possibilities for future applications, such as anticancer reconstruction bone substitutes.