Methods of sealing an injection site of a tissue are provided, where therapeutic agent has been injected into tissue, resulting in increased efficiency or agent uptake. Also provided are methods for delivering therapeutic agent to a tissue, which include injecting a therapeutic agent into a tissue and subsequently sealing the injection site, or engaging an injection device with the tissue for a sufficient period of time that sealing is not necessary to avoid leakage of the therapeutic agent. In one embodiment radio frequency cautery is used to seal the injection site upon needle removal from the tissue. In other embodiments, the injection site is sealed by resistance heating, laser heating or plugging the site with a solid plug or coagulating material at the site.