Aim: To investigate the role of self-emulsifying lipids and porous silica particles in enhancing supersaturated drug loading and biopharmaceutical performance of nanostructured silica-lipid hybrid (SLH) systems. Materials methods: Two lovastatin (LOV)-SLHs were engineered from self-emulsifying lipid (Gelucire? 44/14; Gattefosse, Lyon, France) and Aerosil? 380 (SLH-A; Evonik Industries, Essen, Germany) or Syloid? 244FP silica (SLH-S; Grace Davison Discovery Sciences, Rowville, Australia). Results discussion: The LOV-SLHs encapsulated LOV at 10 w/w, which is =3-fold higher than typical lipid formulations in the absence of porous silica. The LOV-SLHs retained self-emulsifying lipid-associated solubilization benefits and improved drug solubilization by twofold in simulated intestinal condition. SLH-S, with larger surface area (299 m2/g), was superior to SLH-A (184 m2/g) in optimizing oral bioavailability, suggesting a critical role of the silica geometry. Bioavailability of SLH-S was 2.8- and 1.3-fold higher than pure drug and drug suspension in Gelucire 44/14, respectively. Conclusion: In conclusion, SLHs profit from advantages associated with both self-emulsifying lipids and porous silica, and provide potentially improved therapy against coronary artery disease.