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Enhancement of permeability and the retention effect is one of the main pathways for the accumulation of nanomaterials in tumor sites, but poor cellular internalization and rapid clearance of nanomaterials always hamper the efficacy of imaging diagnosis and treatment. With the consideration of both high tumor accumulation and cellular internalization, positively charged nanomaterials can adhere to the tumor cell membrane by an electrostatic force, which is conducive to cellular internalization, but they are easily recognized and cleared during blood circulation. However, negatively charged nanomaterials show an enhanced stealth-like effect and possess a long blood circulation time, which is conducive to tumor accumulation. Therefore, in this work, on the basis of the shielding effect of citrate ions to positive charge and the protonation under an acidic tumor microenvironment, pH-sensitive sodium citrate-modified polyaniline nanoshuttles (NSs) with negative charge during blood circulation but positive charge in tumor sites are designed. With this hierarchical targeting strategy, the blood circulation half-life increases from 4.35 to 7.33 h, and the retention rate of NSs in tumors increases from 5.29 to 8.57% ID/g. Because the retention rate of NSs is increased, the magnetic resonance imaging resolution and signal intensity are significantly improved. A synergistic treatment of tumors is further achieved by means of photothermal therapy with laser irradiation and chemotherapy via heat-stimulated drug release.

Light-cross-linked small-molecule micelles with enediyne units are designed for developing efficient drug-delivery systems. Gemcitabine (GEM) is chosen as a model hydrophilic drug and tethered with a maleimide-based enediyne (EDY) as a hydrophobic tail in the preparation of amphiphilic EDY-GEM. The stable micellar particles are obtained by cross-linking the enediyne moieties via photoinduced Bergman cyclization polymerization in aqueous media. The light-cross-linked spherical micelles with a size of 80 nm are characterized with dynamic light scattering and electron microscopy, showing robust micellar stability, bright fluorescent emission due to their intrinsic conjugated structure, and potential passive tumor-targeting ability through the enhanced permeability and retention effect. The drug-loaded micelles, as an example of light-cross-linked small-molecule micelle-based drug-delivery system, exhibit high drug-loading contents (50%) and greatly improved cytotoxicity toward A549 cells (decreasing the IC50 value of Gemcitabine by 10 times), thanks to the greatly increased cellular uptake of the drug-loaded micelles as confirmed by confocal laser scanning microscopy. The light-cross-linked enediyne-based small-molecule micelles system therefore provides a simple yet efficient drug-delivery platform for cancer chemotherapy.