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Improving low transfection efficiency associated with nonviral vectors is crucial to utilize their advantages (e.g., low safety and manufacturing concerns) over viral vectors. Bioavailable polyamines (e.g., protamine sulfate [PS] and spermine [SPM]), attractively interact with nucleic acids but usually result in low transfection efficiency due to poor intracellular processes and limited complexation capability. In this study, PS/DNA and SPM/DNA polyplexes were shelled with an acid-degradable polyketal (PK) layer via surface-initiated photopolymerization. The resulting polyamine/PK core-shell nanoparticles have gene-carrying polyamine/DNA polyplex core shielded by PK shell, mimicking a viral vector consisting the gene-carrying capsid core and an outer envelope. The PK shell hydrolyzes at an endosomal pH, exposing the polyplex core that is further disassembled by heparan sulfate. Significantly enhanced transfection efficiency by the polyamine/PK core-shell nanoparticles, compared with that of corresponding polyamine/DNA polyplexes, was achieved. Confocal microscopy revealed efficient DNA release from the PS/PK core-shell nanoparticles into the nucleus and substantially increased cellular uptake of SPM/PK core-shell nanoparticles. In addition, lyophilized polyamine/PK core-shell nanoparticles showed preserved transfection capability. In conclusion, addition of an acid-degradable PK shell significantly improved cellular internalization and intracellular trafficking of polyamine/DNA polyplexes, resulting in enhanced transfection.