Nanomedicine has been an intensive research area for decades. Despite the immense research output, the translation of nanoparticle-based formulations into clinics has been limited. The efficient clinical translation of nanomedicine is impeded by several bottlenecks that include low targeting efficiency, imprecise size control, lack of scalable fabrication, rigorous stability requirement, and complicated manufacturing process. The common focus of the studies here is to address these bottlenecks by developing novel nanoparticle systems which are better positioned for clinical translation. The dissertation specifically describes the experimental studies to develop i) a gold nanoparticle system with fine particle size tuning and superb biosafety and ii) a polymeric nanoparticle system with instant nanoformulation capability and enhanced intracellular delivery efficiency. In the first system, a novel process-engineered fabrication method synthesizing sub-10 nm ultrasmall gold nanoparticles (uGNPs) with precise particle size control was achieved. The obtained uGNPs series exhibited size tunability at the nanometric resolution and well-defined physiochemical properties. A collection of in vitro and ex vivo analyses was performed to confirm their biosafety in cytotoxicity, immune compatibility, and blood compatibility. In the second system, an instantly formed polymeric nanoparticle delivery system using a polyelectrolyte coacervate system was created to achieve the facile fabrication of nanomedicine. Nanosized coacervates were successfully formulated with a pair of polyelectrolytes and a chemotherapeutic drug. With the intracellular trafficking properties provided by the assembly components, the coacervate system shows enhanced intracellular delivery. The two novel nanoparticle systems contribute to the progression in tackling the bottlenecks by achieving precision in size control and facile fabrication. The uGNPs system with fine size tuning and excellent biosafety can be utilized to modulate pharmacokinetics and clearance profiles. The controlled stepwise synthesis also has great potential for the large-scale production of uGNPs. The nanocoacervate system, on the other hand, demonstrates the feasibility of instant nanoformulation of drugs using the complex coacervation process. This method can be employed to bypass the special requirement of large-scale production and elongated shelf life of nanomaterials for various applications. Both systems illustrate great potential in clinical translation and can serve as platforms for creating next-generation vaccines, chemotherapeutics, imaging agents, and theranostic agents.