At a time when the term nanotechnology rightly dominates the perception of science, it is not surprising that the scientific community has used this technology to produce lipidpolymer hybrid particles. In this regard, the main motivation is to reach the nanoscale and develop some novel and innovative processes for efficient large-scale production. To this end, some non-conventional two-step processes (or advanced processes) have been proposed in the literature, including spray drying and particle forming by soft lithography. For example, in 2006, Hitzman and co-workers investigated the synthesis of hybrid core-shell nanocarriers using the spray-drying method. In this technique, polymeric nanoparticles prepared by a spray dryer were dispersed in a lipid suspension, and then hybrid core-shell nanocarriers were prepared by spray drying. Since the hybrid nanocarriers were obtained with a wide range of particle sizes (850-1190 nm), it was very conclusive that the nanoscale was not within reach . A few years later, Li et al. and Buchi Labortechnik AG developed a new spray drying technique -the Buchi Nano Spray Dryer. With this method, it was possible to reduce the particle size to 450-500 nm . However, much smaller particles are required for localization in certain tissues; this will be discussed in the corresponding section. Another unconventional technique is particle replication in non-wetting templates (PRINT), developed by . In this fabrication technique, the biomaterial (e.g., siRNAs) is encapsulated and the polymer were dissolved in an organic solvent such as dimethylformamide (DMF) or dimethyl sulfoxide (DMSO) and poured onto a polyethylene terephthalate film (PET). The film was then heated while in conformal contact with a PRINT mold containing 80-320 nm patterns. In this way, the polymer flowed into the mold and cured at a temperature above room temperature, whereupon the polymeric core of the system formed.