Poly(alkylideneamine) Dendrimer Nanogels Codeliver Drug and Nucleotide To Alleviate Anticancer Drug Resistance through Immunomodulation

The development of drug delivery strategies with the desired immunomodulation effects to alleviate tumor drug resistance remains a challenge. Herein, low-generation poly-(alkylideneamine) dendrimer nanogels (DNGs) were developed to codeliver chemotherapeutics 5-fluorouracil (5-FU) and immune agonist cyclic GMP-AMP (cGAMP) for tumor chemoimmunotherapy. The DNGs possess a hydrodynamic size of 145.6 nm, excellent drug/nucleotide coloading capacity, and pH-sensitive drug release profile. The 5-FU-loaded DNGs can overcome 5-FU resistance through prolonged cellular retention and downregulation of P-glycoprotein expression on the cancer cell surface. Meanwhile, the cGAMP in the codelivery system can activate the stimulator of interferon genes pathway in cancer cells, which further relives drug resistance and modulates tumor microenvironment through maturation of dendritic cells and macrophage M1 polarization. The immunomodulation-facilitated drug resistance alleviation was confirmed in vivo in a subcutaneous colorectal tumor mouse model, leading to relatively long tumor drug retention, inhibition of tumor growth, and generation of active antitumor immune responses.