Spatiotemporally-controlled hydrophobic drug delivery via photosensitizer-driven assembly-disassembly for enhanced triple-negative breast cancer treatment

Therapeutic approaches for triple-negative breast cancer (TNBC) have been continuously advancing, but inadequate control over release behavior, insufficient tumor selectivity, and limited drug availability continue to impede therapeutic outcomes in nanodrug systems. In this study, we propose a general hydrophobic antineoplastic delivery system, termed spatiotemporally-controlled hydrophobic antineoplastic delivery system (SCHADS) for enhanced TNBC treatment. The key feature of SCHADS is the formation of metastable photosensitive-antineoplastic complexes (PACs) through the self-assembly of hydrophobic drugs driven by photosensitive molecules. With the further decoration of tumor-targeting peptides coupled with the EPR effect, the PACs tend to accumulate in the tumor site tremendously, promoting drug delivery efficiency. Meanwhile, the disassembly behavior of the metastable PACs could be driven by light on demand to achieve in situ drug release, thus promoting chemotherapeutics availability. Furthermore, the abundant ROS generated by the photosensitizer could effectively kill tumor cells, ultimately realizing an effective combination of photodynamic and chemotherapeutic therapy. As an exemplary presentation, chlorin e6 has been chosen to drive the formation of PACs with the system xc− inhibitor sorafenib. Compared with pure drug treatment, the PACs with the above-described preponderances exhibit superior therapeutic effects both in vitro and in vivo and circumvent the side effects due to off-target. By manipulating the laser irradiation, the PACs-treated cell death mechanism could be dynamically regulated, thus providing the potential to remedy intrinsic/acquired resistance of tumor. Collectively, this SCHADS achieves spatio-temporal control of the drug that greatly enhances the availability of anticarcinogen and realizes synergistic antitumor effect in TNBC treatment, even ultimately being extended to the treatment of other types of tumors. A universal spatiotemporally-controlled hydrophobic antineoplastic delivery system via a photosensitizer-driven assembly-disassembly process was developed for enhanced treatment of TNBC. The photosensitive-antineoplastic complexes (PACs) could be precisely delivered to the tumor site via targeted guiding and EPR effect. In the presence of light, PACs disassemble in tumor sites leading to enhanced drug availability in situ. Notably, the photosensitive molecule generates abundant ROS and the antineoplastic drug suppresses