Breast cancer remains a leading cause of morbidity and mortality among women worldwide, emphasizing the urgent need for enhanced diagnostic and therapeutic approaches. Leucine-rich-alpha-2-glycoprotein 1 (LRG1) has emerged as a notable target due to its markedly elevated expression in breast tumors, suggesting the viability of LRG1 as a theranostic target. In our study, we employed phage display technology to identify a peptide, termed ET, that binds to LRG1 with a dissociation constant of 48.4 μM. After modified with fluorescent cyanine dye, the ET peptide showcased effective tumor-targeting imaging across three different primary breast tumor models and a metastatic breast tumor model. We also undertook a comprehensive safety evaluation, which verified the good biosafety credentials of ET peptide. In summary, the ET peptide identified in this study shows effective LRG1-targeting ability both in vitro and in vivo, thus exhibiting immense potential for clinical translation.

Chemotherapy remains one of the irreplaceable treatments for cancer therapy. The use of immunogenic cell death (ICD)-inducing chemotherapeutic drugs offers a practical strategy for killing cancer cells, simultaneously eliciting an antitumor immune response by promoting the recruitment of cytotoxic immune cells and production of granzyme B (GrB). However, numerous malignant cancers adaptively acquired the capacity of secreting serpinb9 (Sb9), a physiological inhibitor of GrB, which can reversibly inhibit the biological activity of GrB. To circumvent this dilemma, in this study, an integrated tailor-made nanomedicine composed of tumor-targeting peptide (Arg-Gly-Asp, RGD) decorated liposome, doxorubicin (DOX, an effective ICD inducer), and the compound 3034 (an inhibitor of Sb9), is developed (termed as D3RL) for breast cancer chemo-immunotherapy. In vitro and in vivo studies show that D3RL can directly kill tumor cells and trigger the host immune response by inducing ICD. Meanwhile, D3RL can competitively relieve the inhibition of Sb9 to GrB. The restored GrB can not only effectively induce tumor immunotherapy, but also degrade matrix components in the tumor microenvironment, consequently improving the infiltration of immune cells and the penetration of nanomedicines, which in return enhance the combined antitumor effect. Taken together, this work develops an integrated therapeutic solution for targeted production and restoration of GrB to achieve a combined chemo-immunotherapy for breast cancer.

Traditional surgical treatment is difficult to thoroughly remove esophageal squamous cell carcinomas (ESCC), and postoperative recurrence caused by residual tumor cells is a critical factor in the poor prognosis. Since surgical resection promotes the local angiogenesis at the tumor site, further exacerbating the proliferation and invasion of residual tumor cells, it is urgent to inhibit angiogenesis after surgery. Here, a functional peptide-based nanomedicine was obtained from peptide–drug conjugates, which are composed of a hydrophilic targeting motif (vascular endothelial growth factor family and their receptors (VEGFR) targeting peptide for anti-angiogenesis), and an ester-linked hydrophobic oridonin (ORI). The nanomedicine exhibits esterase-catalyzed disassembly and drug release, and significantly enhanced the anti-tumor efficacy of chemotherapeutics in a postoperative tumor recurrence model through synergistic anti-angiogenic strategies. This study provides an integrated solution for anti-angiogenesis-augmented chemotherapy and demonstrates the encouraging potential for postoperative treatment.