Pharmaceutical technology has advanced significantly with the advent of polymer-based nanocarriers, transforming drug delivery by enabling controlled release, improved bioavailability, and targeted delivery to specific tissues or cells. These systems, engineered at the molecular level, facilitate the encapsulation and precise targeting of a wide range of therapeutics, including drugs, proteins, and nucleic acids. This has led to more effective treatments for complex diseases. However, translating these polymeric vehicles into clinical applications remains challenging due to the complex biological environments they must navigate. Overcoming extracellular barriers like the extracellular matrix and intracellular obstacles such as lysosomal degradation requires sophisticated polymer designs and advanced strategies to ensure both stability and effective cargo delivery. My dissertation explores these challenges through the engineering of guanidinium-functionalized poly(oxanorbornene)imide (PONI-Guan) polymers for the efficient delivery of therapeutics into the cytosol. I developed PONI-Guan-based nanoparticles with varying structural configurations to optimize their hydrophobicity and surface characteristics, enabling targeted delivery for anti-inflammatory and anti-cancer therapies. Additionally, I expanded the PONI-Guan polymer library to improve siRNA delivery efficiency and explored a gelatin-based nanoemulsion system for macrophage polarization. These studies collectively demonstrate the potential of polymeric nanomaterials for therapeutic delivery, offering promising solutions for overcoming the challenges associated with drug delivery in complex biological systems.