Virus-like particles (VLPs) comprise the structural components of a virus that are recombinantly expressed as self-assembling, non-infectious particles. The development of VLPs for biomedical applications is of interest due to their improved safety profile and ease of production compared to live viruses. The first recombinant VLP-based vaccine was approved for human papillomavirus (HPV) in 2009, and many more have since been approved or are in clinical development. VLPs are also of interest for applications such as drug delivery, but they need to be further engineered with new functionalities for cargo encapsulation, release, and targeting. Throughout this work, we describe the advancements in the development of VLPs for drug delivery applications as well as the engineering of bacteriophage MS2-based VLPs for improved cellular uptake and drug delivery. Using the single amino acid fitness landscape of the MS2 coat protein, we were able to design locally supercharged mutants with positive surface charge and increased cellular uptake. The biophysical properties and biological activity of the best-performing mutants were characterized, and mutant capsids were able to deliver a cytotoxic cancer drug in cell culture with greater than 50-fold increases in efficacy compared to wild-type MS2 in proof-of-concept drug delivery experiment. To study the effects of particle size on cellular uptake, we created a new set of locally supercharged MS2 variants combined with a single point mutation that was previously shown to create smaller capsids. These engineered triple mutants retained their ability to internalize and deliver small-molecule drugs into mammalian cells, but exhibited increased thermal stability and unexpected assembly geometries. Through experimental measurements and computational predictions, we investigate how these mutations at the VLP interfaces affect particle size and stability. This work demonstrates the utility of genetic screening methods such as fitness landscaping for VLP engineering and explores the use of biophysical and in silico characterization methods to assess VLP properties and function for biomedical applications