An acid-degradable polymer-caged lipoplex (PCL) platform consisting of a cationic lipoplex core and a biocompatible, pH-responsive polymer shell has been developed for the effective delivery of small interfering RNA (siRNA) through a combination of facile loading, rapid acid-triggered release, cellular internalization, and effective endosomal escape. In vitro testing of this degradable PCL delivery platform reveals similar to 45 and similar to 2.5-fold enhancement of enhanced green fluorescent protein knockdown in cancer cells in comparison to either free siRNA or siRNA-loaded non-acid-degradable lipoplex formulations, respectively.