Complex diseases often arise from intricate interactions between genetic predispositions and environmental factors, leading to cellular dysfunctions that manifest across a range of pathological conditions. Addressing these multifactorial challenges necessitates innovative therapeutic strategies capable of simultaneously targeting multiple disease pathways. This thesis explores the development and optimization of versatile nanosystems designed for protein delivery and scavenging of pro-inflammatory factors, aimed at treating diverse and complex conditions. The research introduces three distinct approaches: (1) the development of a polymeric nanosystem for oral delivery of the pegfilgrastim protein as a radiation countermeasure for hematopoietic acute radiation syndrome (H-ARS); (2) the adaptation of this polymeric nanosystem for glucose-responsive, antibacterial, and antioxidant treatment of diabetic wounds; and (3) the creation of a 2D nanosheet for scavenging small extracellular vesicles (sEVs), aimed at mitigating metastasis in triple-negative breast cancer post-radiotherapy. These studies utilized a combination of material synthesis, advanced characterization techniques, and delivery strategies to enhance the therapeutic functionality of the delivered cargos. For H-ARS, the polymeric nanosystem was engineered to improve bioavailability and enable controlled release, ensuring effective oral delivery of the PF protein. The glucose-responsive polymeric nanosystem, encapsulated within a P(NIPAm-co-AAc) hydrogel, facilitated responsive release under high glucose conditions, scavenging cell-free DNA and reactive oxygen species, while inhibiting bacterial growth to accelerate wound healing in mouse models. Additionally, the 2D cationic nanosheet was designed to capture and neutralize tumor-derived small extracellular vesicles (sEVs), reducing their role in metastasis and enhancing therapeutic outcomes following radiotherapy in breast cancer models. The findings from these investigations demonstrate the significant therapeutic potential of the engineered nanosystems across three distinct disease models. The rational design of these nanocarriers addresses several key challenges in contemporary medicine, including the highly challenging oral delivery of proteins, the intricate process of diabetic wound healing, and the suppression of radiotherapy-induced metastasis. This dissertation not only bridges a critical knowledge gap regarding the strategic deployment of nanomaterials to overcome these complex pathological conditions but also contributes to the development of advanced tools for the next generation of precision medicine. By elucidating how nanosystems can be systematically optimized for specific therapeutic applications, this work provides a foundation for innovative approaches that could enhance treatment modalities across a spectrum of diseases.