Drug delivery through the oral pathway is the most common method for systemic absorption of therapeutics as well as treatment of gastrointestinal conditions. However, non-site-specific methods face challenges in achieving targeted delivery, leading to drug accumulation, toxicity, in undesired areas. Further, diseases which require more targeted delivery in specific regions of the GI tract have necessitated methods in which localized delivery is achieved. To address these issues, researchers have developed different methods for achieving targeted dissolution of drugs in specific regions of the GI tract by taking advantage of localized physiological properties at desired areas, including motility, pH profile, and microbial diversity. Within this report, different approaches for targeted polymer dissolution are reviewed for advantages such as targeting efficacy and disadvantages such as complexity of approach. Further, the efficacy of targeting is also studied by assessing the in vitro-in vivo correlation to analyze whether the drug formulation will exhibit similar targeting performance in vivo. To study this, methods such as blood plasma sampling and in vivo imaging techniques, including gamma scintigraphy, MRI scans, X-ray radiography etc. are analyzed further. Based on these findings, it was determined that the optimal delivery approach requires combining different strategies to maximize targeting efficiency. One such method showing promising targeting capabilities was the combination of a pH sensitive polymer and a microbially responsive polysaccharide, allowing for higher targeting specificity within a larger population of subjects while reducing the effects of variability. To validate this, in a preliminary study, a polymer blend of a polysaccharide (lactulose) and pH sensitive polymer (cationic polymethacrylate polymer), were combined to perform colonic sampling for use with a preexisting smart sampling capsule platform. To identify the optimal blend ratio and quantify microbial site selectivity for colonic targeting, different in vitro tests were conducted, and the promising results demonstrated the efficacy of the created polymeric blend for colonic targeting. The future steps of this study highlight the need for validating the in vivo performance of the devised targeting mechanism, and by combining it with tracers to enable in vivo imaging, the site selectivity and effective sealing of the capsule can be verified.