Synthetically Tunable Suprahybrid Nanoparticle Platform for the Efficacious Delivery of Therapeutics.

The discovery of lipid-hybrid nanosystems has offered potential solutions to various drug delivery and theranostic challenges. However, in many instances, the commonly used lipids and other components in these systems often pose challenges related to their solubility, physicochemical properties, immune compatibility, and limited synthetic tunability. In this work, we introduce a synthetically tunable supramolecular scaffold with amphiphilic characteristics based on the calix[4]arene macrocyclic system. We designed and synthesized two novel calix[4]arene-polyethylene glycol (PEG) conjugates, termed Cal-P1 and Cal-P2, and these were characterized utilizing a wide range of spectroscopic and analytical methods. The rational design of Cal-P1 and Cal-P2 demonstrates their utility in forming stable blended nanospheres with sustained drug release characteristics. The synergistic blending of PLGA and the calixarene scaffold (Cal-P1 and Cal-P2) in constructing long-lasting and controlled-release nanoparticles (NPs), which are optimized for encapsulating Nile Red dye, and their successful internalization and retention in HeLa cancer cells are demonstrated through in vitro assays. The potential of these NPs as sustained therapeutic carriers is investigated in vivo, showing improved retention compared to free dye with negligible toxicity. The successful design and construction of Cal-P1 and Cal-P2 nanosystems represent a new paradigm for addressing drug loading challenges, opening up opportunities for the development of highly efficient, synthetically tunable alternative adjuvants for drug encapsulation and delivery.