Colorectal cancer peritoneal metastasis (CRC-PM) has the poorest prognosis compared to other metastasis sites. It is often considered an end-stage as malignant tumors are difficult to completely eradicate and have a high recurrence rate of carcinomatosis. Recently, the combination of cytoreductive surgery (CRS) with intraperitoneal (IP) therapy (CRS-IP) has emerged as a promising modality and has shown improvements over traditional intravenous (IV) therapies. Both the fast absorption of chemotherapeutic drugs during IP therapy, which results in impaired accumulation at the tumor site, and the use of toxic solubilizer Cremophor EL impedes the widespread application of IP therapy. Although current drug delivery systems have shown promising results, due to the hydrophobicity, moderate biocompatibility, and instability in peritoneal cavity and plasma environment, they fail to fully address the limitation during IP treatment. Chapter 1 comprehensively introduced the anatomical background of the colon, rectum, peritoneum, and its microenvironments, followed by the mechanisms of CRC and CRC-PM. Furthermore, Chapter 1 covered the current treatments and their associated limitations, along with an investigation of current nanotechnology-based advancements in IP treatment field. In Chapter 2, we introduced a novel PLGA lipid nanoparticle (PLGA lipid NP) to address the limitations of current drug delivery system since it combines the advantages from each component: structural integrity from PLGA polymer, high biocompatibility from lipids, and low immunogenicity from PEGylated lipids (lipids modified by polyethylene glycol). Our goal is to optimize retention time, penetration capability, stability, and efficacy to maximize the overall outcome of IP therapy. We employed PTX as a model chemotherapeutic drug to evaluate the effectiveness of our drug delivery system. We described the synthesis and mechanism of three PTX delivery vehicles: PTX encapsulated in PLGA lipid NP (PTX-PLGA lipid NP), PTX encapsulated in Cremophor EL/ethanol micelle (PTX-Cre Micelle, current formulation in clinical use), and free PTX dissolved in DMSO or ethanol solvent (Free PTX). In Chapter 3, we verified the successful coating of the lipid layer by dynamic light scattering (DLS), zeta potential analysis, and transmission electron microscopy (TEM). In addition, we performed in vitro experiments to assess the physicochemical properties of each vehicle, including in vitro release profiles and stability tests in different biological environments. We showed improved stability and enhanced sustained release of the PLGA lipid NP. Furthermore, cell-based assays indicated that the PTX-PLGA lipid NP exhibited an enhanced cellular uptake profile with an IC50 value comparable to canonical formulations. In Chapter 4, we used plasma pharmacokinetics (PK) and biodistribution (BD) in major organs and tumor tissue to study the outcome of IP therapy from different PTX formulations. Both PK and BD studies revealed that the PLGA lipid NP formulation resulted in a substantial accumulation of the drug in both the tumor and the circulatory system, demonstrating that the PLGA lipid NP can facilitate the drug accumulation through both direct disposition within the peritoneal cavity and indirect pathway via the circulatory pathway. Furthermore, survival curve analysis showed an improved antitumor effect from PLGA lipid NP, without inducing significant toxicity in mice.