This review describes studies on drug discovery using a rational formulation design and innovative, drug delivery systems (DDS) for biomaterials such as therapeutic peptides and nucleotides. The microcapsules of the LH-RH superagonist leuprorelin acetate prepared using the new in-water drying method and biodegradable polymers, such as PLGA and PLA, could achieve a long-term sustained release for 1-6 months thereby facilitating easily treatment of hormone-dependent diseases, prostate cancer, endometriosis, and precocious puberty. This DDS technology showed an improvement in patient QOL and highly promoted the clinical value of the agonist. Moreover, PLGA microcapsules of siRNAs against VEGF, cFLIP, Raf-1, and Int6 have also been developed to treat various cancers and arteriosclerosis obliterans. To develop therapeutic nucleotides, a particle design is created using functional peptides, such as cell penetrating peptides (CPP), nuclear localizing signals (NLS), tight junction reversible openers (AT1002), bombesin, and dynein light chain-associated sequences. siRNA use should lead to a paradigm shift in drug discovery against various diseases. Tat analog with NLS could enhance the potency of a vaginal DNA vaccine. The artificial Tat CPP of STR-CH₂R₄H₂C synthesized in our laboratory could efficiently deliver siRNAs into many types of cells and enhance the therapeutic effects for treating sarcoma, atopic dermatitis, allergic rhinitis, and asthma by intratumor injection and inhalation of the nanoparticles. Tat and AT1002 analogs used to treat atopic dermatitis in mice increased cell membrane permeability to siRelA, a siRNA against a subclass of NF-κB, and exhibited striking therapeutic and preventive effects.