Protein nanocages have been explored as potential carriers in biomedicine. Formed by the self-assembly of protein subunits, the caged structure has three surfaces that can be engineered: the interior, the exterior and the intersubunit. Therapeutic and diagnostic molecules have been loaded in the interior of nanocages, while their external surfaces have been engineered to enhance their biocompatibility and targeting abilities. Modifications of the intersubunit interactions have been shown to modulate the self-assembly profile with implications for tuning the molecular release. We review natural and synthetic protein nanocages that have been modified using chemical and genetic engineering techniques to impart non-natural functions that are responsive to the complex cellular microenvironment of malignant cells while delivering molecular cargos with improved efficiencies and minimal toxicity.

Hyperpigmentation is a major cosmetic concern that results from the overproduction of melanin from melanocyte cells in the skin. Current formulations of therapeutic drugs and active molecules that are intended to be delivered to the melanocytes are not targeted, leading to inefficient delivery and undesirable side effects. There is a compelling need for delivery vehicles that target melanocytes to effectively regulate melanin production. Self‐assembling protein nanocages (PNCs) have been shown to offer safe and efficient delivery of active molecules. They are versatile protein nanoparticle platforms that can be engineered to display functional ligands to impart specific biological functions. In this work, E2 PNCs are engineered to display alpha‐melanocyte‐stimulating hormone (AlphaMSH) peptides as ligands for targeting and enhancing uptake by melanocytes. At 500 pM, the AlphaMSH‐modified E2 PNCs show 4‐fold increase in melanocyte cell uptake compared to bare E2 PNCs in 2 hours. This increase was less pronounced in keratinocytes. Competitive inhibition assay proves that the MC1R melanocyte cell surface receptor facilitates the uptake of E2 PNCs by mediating interaction with the displayed AlphaMSH peptides. PNCs can thus be used as targeted delivery vehicles of drugs and active molecules to melanocytes for the management of hyperpigmentation.