Sequential lysosome-microtubule targeted transformable nanosystem for long-lasting photodynamic-based multimodal therapy of breast cancer.

Abstract

Subcellular organelle-targeted strategies hold great promise in cancer therapy. Peptide nanofibers can induce lysosomal membrane permeabilization (LMP) and microtubule disruption, yet their in vivo delivery remains challenging. Here, we report a matrix metalloproteinase-2 (MMP-2)-responsive shape transformable nanosystem (CpA) that self-assembles from the amphiphilic conjugate Ce6-pep-iABS, comprising the photosensitizer chlorin e6 (Ce6) and the carbonic anhydrase IX (CA IX) inhibitor 4-(2-aminoethyl) benzenesulfonamide (ABS) linked via an MMP-2-cleavable peptide. Upon reaching tumors, CpA transforms from spherical nanoparticles into nanofibers, enabling deep penetration and long-term retention in tumor. The released ABS segments continuously inhibit CA IX to reverse extracellular acidosis and alleviate immunosuppression. Crucially, the transformed nanofibers exhibit enhanced cellular uptake and induce sequential LMP and microtubule disruption, which synergizes with photodynamic therapy (PDT) to amplify immunogenic cell death (ICD), activate robust antitumor immunity, and establish long-lasting immunological memory. This synergistic effect significantly inhibits tumor growth and prevents tumor recurrence and metastasis, presenting an innovative paradigm for multimodal cancer therapy by integrating sequential organelle targeting, tumor microenvironment modulation, and intensified PDT.