A biotin-functionalized calix[4]arene nanocarrier with intrinsic antitumor activity for combined chemo-photodynamic therapy

A multifunctional pH‑responsive calix[4]arene‑based carrier CMP with dual hydrophobic alkyl substituents and biotin‑PEG chains was constructed for co‑delivery of DOX and Ce6. • The blank calixarene matrix acts as a supramolecular chemotherapeutic agent with certain intrinsic antitumor activity, while co-loaded DOX and Ce6 elicit prominent in vitro chemo-photodynamic suppression. • The biotin‑targeted DOX@CMP@Ce6 nanosystem achieves potent in vivo tumor inhibition along with favorable biosafety. Conventional nanoplatforms often suffer from complicated fabrication, poor structural controllability, insufficient tumor targeting, and unsatisfied therapeutic efficacy. To address these issues, herein we rationally design and construct a novel calix[4]arene derivate CMP, whose upper rim is functionalized with pH-responsive biotin-PEG hydrophilic chains, and lower rim is dually modified with hydrophobic alkyl chains and antitumor pharmacophores. This “all-in-one” supramolecule can not only serve as an excellent supramolecular chemotherapeutic agent itself, but also act as a versatile carrier to co-deliver doxorubicin (DOX) and chlorin e6 (Ce6). The nanoplatform therefore integrates two types of chemotherapeutic modalities and biotin-targeted photodynamic therapy for multi-modal tumor treatment. Notably, in vivo experiments demonstrate that the resultant DOX@CMP@Ce6 nanosystem achieves a 90.5% tumor growth inhibition rate, while displaying biotin-mediated tumor tropism, excellent biocompatibility, and robust triple-modality combinatorial therapeutic effects. Collectively, this work provides key insights into the rational construction of multifunctional supramolecular platforms, reinforcing the broad prospects of calixarene derivatives for nanomedical applications.