A β-cyclodextrin-based supramolecular modular system creating micellar carriers for codelivery of doxorubicin and siRNA for potential combined chemotherapy and immunotherapy

The combination of chemotherapy and gene therapy holds promise in treating cancer. A key strategy is to use small interfering RNAs (siRNAs) to silence programmed death-ligand 1 (PD-L1) expression in cancer cells, disrupting tumor immune evasion and enhancing anticancer treatments, particularly when used in conjunction with chemotherapy drugs such as doxorubicin (Dox). However, effective codelivery of drugs and genes requires carefully designed carriers and complex synthesis procedures. To address this challenge, we propose a convenient modular self-assembly system for creating multifunctional micellar carriers that can efficiently codeliver both Dox and siRNA, where micelles are formed by cationic amphiphilic supramolecular architectures that are constructed through host–guest interactions between β-cyclodextrin (β-CD) and adamantane (Ad) to incorporate various functional polymer segments, such as low-molecular-weight polyethylenimine (oligoethylenimine, OEI), poly(ethylene glycol) (PEG), and polycaprolactone (PCL), at adjustable ratios. The supramolecular micellar carrier systems can be easily optimized to achieve excellent structural stability, drug and gene loading, and delivery efficiency, resulting in significant anticancer effects from Dox delivery and simultaneous inhibition of PD-L1 due to the siRNA delivery. Therefore, this modular supramolecular strategy offers a sophisticated, adaptable, and straightforward approach to creating multifunctional micellar carriers, with potential for drug- and gene-based immune-assisted cancer therapy.