Poly(beta-amino esters) and poly(amido amine) are important class of biodegradable polymers useful for biomedical applications. Synthesis of amphiphilic conetwork (APCN) gels and hydrogels of these polymers with controlled composition, degradation, and release behaviour is desirable. Herein, we report a strategy for the synthesis of multi-responsive APCN gels of poly(caprolactone) (PCL) and poly(beta-amino esters) or poly(amido amine) with tunable degradability. The APCN gels were synthesized by the sequential nucleophilic substitution reaction between activated halide terminated PCL and poly(ethylene glycol) (PEG)-based poly(beta-amino ester) or poly(bis-acrylamide)-based poly(amido amine) prepolymer containing amine moieties in the backbone or side chain. A model APCN gel obtained by reacting halide terminated PCL and mixture of poly(beta-amino esters) and di-thiolated poly(amido amine) exhibited triggered degradation and release of drugs in acidic, basic, enzymatic, and slightly reducing environments whereas showed low level of release under normal physiological condition. The properties of this APCN gel were compared with a model hydrogel consisting of PEG and poly(amido amine). These types of gels are hemocompatible and useful for the controlled release and tissue engineering applications. (C) 2017 Elsevier Ltd. All rights reserved.