Nucleus-targeted therapy holds great promise in cancer treatment; however, a lack of effective nucleus-specific delivery significantly limits its application potential. Here, we report a nucleus-targeted synergistic chemo-photodynamic therapy based on the self-assembly of chlorin e6 (Ce6) and doxorubicin (DOX) tuned by clickable dibenzocyclooctyne (DIBO) functionalized lysine (D-K) and subsequent reaction with crosslinkers. The assembled nanodrugs with high loading efficiency and long-term stability show enhanced cellular uptake and accumulation in the nucleus, resulting in greatly improved in vitro and in vivo chemo-photodynamic efficacy. Notably, D-K can promote the rapid self-assembly of Ce6 and DOX in aqueous solution, avoiding the introduction of organic solvents or tedious preparations. In addition, the introduction of the DIBO group can effectively expand the types of self-assembly material and enhance the self-assembly behaviour through a copper-free click reaction. Therefore, we present an effective nucleus-targeted combination drug delivery strategy, which has great potential in the treatment of many diseases.

Subcellular organelle targeted transport is of great significance for accurately delivering drugs to active sites for better pharmacological effects, but there are still a lot of challenges due to transport problems. In addition, the killing effect of one kind of drug on cells is limited. Therefore, it is necessary to develop a multifunctional nanoplatform that can co-deliver synergistic therapeutic agents. Here, we prepare a simple amphiphilic nanocarrier (LC) with rapid endosomal escape ability for nucleus-selective delivery of hydrophilic active protein deoxyribonuclease I (DNase I) and hydrophobic anticancer drug doxorubicin (DOX). LC has been applied to effectively encapsulate DNase I just by simply mixing their aqueous solutions together. In addition, DOX modified with adamantane groups via a redox-responsive linker is incorporated into the architecture of DNase I nanoformulations through host–guest interaction. This multi-component nanoplatform can quickly escape from the endolysosomes into the cytoplasm and make DNase I and DOX highly accumulate in the nucleus and consequently induce strong synergistic anticancer efficacy both in vitro and in vivo. This work illustrates a new platform for codelivery of proteins and drugs that target subcellular compartments for functions.

A multiplex miRNA detection scheme with simultaneous multiple signal output by single excitation has been reported.