Genetic vaccination using plasmid DMA presents a unique opportunity for achieving potent immune responses without the potential limitations of many conventional vaccines. Here we report the design of synthetic biodegradable polymers specifically for enhancing DNA vaccine efficacy in vivo. We molecularly engineered poly(ortho ester) microspheres that are non-toxic to cells, protect DNA from degradation, enable uptake by antigen-presenting cells, and release DNA rapidly in response to phagosomal pH. One type of microsphere of poly(ortho esters) that releases DNA vaccines in synchrony with the natural development of adaptive immunity, elicited distinct primary and secondary humoral and cellular immune responses in mice, and suppressed the growth of tumour cells bearing a model antigen. This polymer microparticulate system could, with further study, have implications for advancing the clinical utility of DNA vaccines as well as other nucleic-acid-based therapeutics against viral infections and cancer.
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The authors thank Daniel Anderson for valuable discussions and assistance and Frank Miskevich for assistance with confocal microscopy. This research was supported in part by a research grant from AP Pharma. C.W. would like to thank the National Institutes of Health for an individual National Research Service Award (1 F32 GM64921-01). Correspondence and requests for materials should be addressed to R.L. or J.H. Supplementary Information accompanies the paper on www.nature.com/naturematerials