Current clinically approved drug delivery systems, such as liposome, PEGylated liposome, and polymeric micelle, predominantly rely on passive accumulation within tumor tissues by diffusion through the defective tumor vessels during circulation. The targeting efficacy toward cancer cells is very limited due to their inadequate interaction with cancer cells. The attachment of targeting ligands to nanocarriers has demonstrated its effectiveness in enhancing binding affinity and, consequently, facilitating cellular uptake via receptor-mediated endocytosis. However, the conventional methods employed for ligand attachment suffer from harsh conditions, low efficiency, and limited control over ligand orientation. These drawbacks compromise the targeting performance and are believed to result in the current absence of a targeted drug delivery system on the market. In this project, we propose a simple, efficient, and mild attachment method to spontaneously activate on demand nanocarriers. This innovative approach has the potential to have a multi- level effect, first to revolutionize various fields, including drug delivery, diagnostics, and nanotechnology, by providing advanced tools for targeted therapies and diagnostics. Secondly, by developing novel methodologies that can be applied to existing technologies to enhance uptake, localization, and efficacy while minimizing systemic toxicity thus potentially shifting the health- economic balance for some treatments which were previously inaccessible.