Photoswitchable Ultrafast Transactivator of Transcription (TAT) Targeting Effect for Nanocarrier-Based On-Demand Drug Delivery

Nanocarriers with intelligent transactivator of transcription (TAT) targeting properties are of particular interest for on-demand drug delivery in the field of precision nanomedicine. Nevertheless, the key challenge of this strategy is the slowness of activating TAT peptide at the targeted tissue. As a proof-of-concept, polymeric micelles (S)TAT-NPIR&DOX with photoswitchable ultrafast TAT targeting effect are designed and explored. The hydrophilic shell of (S)TAT-NPIR&DOX consists of a TAT-functionalized short-chain poly(ethylene glycol) and a thermoresponsive long-chain polyphosphoester (PPE). In nontumor tissue, the TAT peptide of (S)TATNP(IR&DOX) is masked by long-chain PPE to minimize nonspecific uptake of nanocarriers. Upon near-infrared (NIR) photoactivation, the TAT peptide is ultrafastly reexposed (within 60 s) via the collapse of thermoresponsive PPE, resulting in significantly enhanced cellular uptake of nanocarrier by tumor cells. Such photoswitchable TAT targeting effect efficiently avoids nonspecific uptake by nontumor cells and enhances tumor cell uptake, achieving tumor-specific on-demand drug delivery and superior anticancer efficacy. This approach using NIR light-induced TAT targeting effect can be extended to a variety of applications for on-demand drug delivery, which also provides new avenues for phototargeted drug delivery.