Polydopamine-modified cyclodextrin metal-organic framework for efficient BCL-2 siRNA delivery in lung cancer therapy.

The antiapoptotic protein B-cell lymphoma 2 (BCL-2) is overexpressed in lung cancer, serving as a key mechanism for apoptosis evasion. Therapeutics targeting BCL-2, such as small interfering RNA (siRNA), hold great promise for lung cancer treatment, while delivery challenges hinder the clinical applications of BCL-2 targeting agents. Cyclodextrin metal-organic framework (CD-MOF) is a facile and edible drug delivery carrier with remarkable biocompatibility, which is a suitable candidate for gene delivery. In our study, BCL-2 siRNA (siBCL-2) was loaded into CD-MOFs and subsequently coated by polydopamine (PDA) to form siBCL-2@CD-MOF@PDA nanoplatform. PDA modification creates a protective layer, preventing siBCL-2 from hydrolytic degradation. Results showed CD-MOF@PDA effectively overcame the intrinsic limitations of siRNA and the agarose gel electrophoresis confirmed that CD-MOF@PDA significantly enhanced the stability of siRNA. Western blot results demonstrated that siBCL-2@CD-MOF@PDA markedly reduced the expression level of BCL-2 protein compared with free siBCL-2. In an A549 tumor model, both in vivo and ex vivo biodistribution assays demonstrated the outstanding intratumor retention capacity of siBCL-2@CD-MOF@PDA. Moreover, siBCL-2@CD-MOF@PDA achieved excellent therapeutic effects compared with other groups while maintaining favorable biocompatibility in vivo. This work may provide a potential alternative to precise gene therapy for cancer.