Rational design and facile fabrication of biocompatible triple responsive dendrimeric nanocages for targeted drug delivery

Multi-responsive polymeric nanoparticles have shown great promise in the sufficient site-specific delivery of drugs in heterogeneous and complicated biological microenvironments, but without great success due to many problems such as sophisticated manufacture process, high cost and cytotoxicity. In this work, a novel triple responsive dendrimeric nanocage (TDN) is fabricated through co-assembling and cross-linking of lipoic acid modified low generation dendrimers with lipoic acid modified polyethylene glycols (PEGs). This nanocage exhibits improved drug loading capacity (about 2 times higher) at a lower temperature and stimuli-responsive drug release profile upon the stimulation of temperature, acid pH and reducing agent. More importantly, the nanocage promotes drug internalization, conduces endosomal escape, and realizes intracellular controlled drug release. Furthermore, the nanocage significantly improves the pharmacokinetics and biodistribution of antitumor drugs, confirming the potent in vivo therapeutic effect with reduced side effects. The rational design and facile fabrication of multi-responsive dendrimeric nanocages provide a proof-of-concept for precise targeted drug delivery, and may have great potential for clinical use in the future.