The nanomedicine field has advanced significantly and current progress in nanotechnologies has enabled translational research across therapeutic landscape. Recent trends in clinical studies and FDA approvals have demonstrated the potential of using biologics as therapeutic modalities. Ongoing fundamental research across therapeutic modalities have set foundations to treat multiple diseases, including the ones that were hard-to-cure and assures the promising future of nanomedicine. However, the therapeutic expansion from small molecule drug to biologics comes with their unique delivery challenges. It requires strategic designing of delivery platforms to overcome biological barriers associated with each modality and demands fundamental understanding of formulation factors to predetermine the fate of delivered therapeutics. Each formulation requires stability in blood circulation, ability to reach specific organs or tissue types, have enough tissue penetrations and importantly, and have cytosolic accessibility. These different aspects of delivery challenges can be addressed by tuning formulation properties, and understanding these structural and formulation factors are essential in improving therapeutic efficacy. In this dissertation, we have developed polymeric systems focusing on two different aspects of drug delivery viz, targeted tissue accumulation and cellular internalization. An antibody guided polymeric system is established to address the challenges with current antibody drug conjugates (chapter 2). Then we understood the effect of antibody polymer conjugation process towards cell receptor binding activity by varying polymer molecular weights and number of polymers per antibody (chapter 3). We also designed disulfide-based polymeric nanogel to fundamentally understand the effect of disulfide bonds in endosomal escape (chapter 4). Finally, we designed stimuli-responsive self-immolative protein-PEGylation strategy with terminal disulfide functionality to leverage thiol-mediated internalization of biologics.