Multifunctional D-Type Peptide Dendrimer-Based Nanocarriers Enabling Inherent Autophagy Modulation and Lysosomal Escape for Breast Tumor Therapy

Chemotherapy is often limited by its low efficacy and severe side effects. Autophagy acts as a double-edged sword where high levels can promote cancer cell death, while low levels induced by chemotherapy can reduce therapeutic effects. Herein, we designed a multifunctional D-type peptide dendrimer as a drug delivery system for chemotherapeutic agents. This nanocarrier is designed to significantly reduce the toxic side effects of the drug and, upon internalization into cancer cells, utilizes the dendrimer terminals modified with histidine to achieve efficient lysosomal escape, thereby rapidly releasing the payload and enhancing therapeutic efficiency. We employed transmission electron microscopy (TEM) and Western blot (WB) assays to assess the stronger autophagy-inducing potential of the D-type dendrimers compared with L-type and free chemotherapeutics. Beyond its role as a carrier, the D-type dendrimers further synergize with the encapsulated drug to trigger enhanced autophagy, aiming to enhance therapeutic efficiency. This “Squeezing every ounce of potential” strategy fully leverages the capabilities of the D-type peptide dendrimers, thereby addressing the existing challenges in chemotherapy treatment. This approach suggests a promising therapeutic strategy for the application of chemotherapy.