Craft of Co-encapsulation in Nanomedicine: A Struggle To Achieve Synergy through Reciprocity.

Achieving synergism, often by combination therapy via codelivery of chemotherapeutic agents, remains the mainstay of treating multidrug-resistance cases in cancer and microbial strains. With a typical core-shell architecture and surface functionalization to ensure facilitated targeting of tissues, nanocarriers are emerging as a promising platform toward gaining such synergism. Co-encapsulation of disparate theranostic agents in nanocarriers-from chemotherapeutic molecules to imaging or photothermal modalities-can not only address the issue of protecting the labile drug payload from a hostile biochemical environment but may also ensure optimized drug release as a mainstay of synergistic effect. However, the fate of co-encapsulated molecules, influenced by temporospatial proximity, remains unpredictable and marred with events with deleterious impact on therapeutic efficacy, including molecular rearrangement, aggregation, and denaturation. Thus, more than just an art of confining multiple therapeutics into a 3D nanoscale space, a co-encapsulated nanocarrier, while aiming for synergism, should strive toward achieving a harmonious cohabitation of the encapsulated molecules that, despite proximity and opportunities for interaction, remain innocuous toward each other and ensure molecular integrity. This account will inspect the current progress in co-encapsulation in nanocarriers and distill out the key points toward accomplishing such synergism through reciprocity.