Biomimetic Nanovehicle-Enabled Targeted Depletion of Intratumoral Fusobacterium nucleatum Synergizes with PD-L1 Blockade against Breast Cancer.

Immune checkpoint blockade (ICB) therapy has been approved for breast cancer (BC), but clinical response rates are limited. Recent studies have shown that commensal microbes colonize a variety of tumors and are closely related to the host immune system response. Here, we demonstrated that Fusobacterium nucleatum (F.n), which is prevalent in BC, creates an immunosuppressive tumor microenvironment (ITME) characterized by a high-influx of myeloid cells that hinders ICB therapy. Administering the antibiotic metronidazole in BC can deplete F.n and remodel the ITME. To prevent an imbalance in the systemic microbiota caused by antibiotic administration, we designed a biomimetic nanovehicle for on-site antibiotic delivery inspired by F.n homing to BC. Additionally, ferritin-nanocaged doxorubicin was coloaded into this nanovehicle, as immunogenic chemotherapy has shown potential for synergy with ICB. It has been demonstrated that this biomimetic nanovehicle can be precisely homed to BC and efficiently eliminate intratumoral F.n without disrupting the diversity and abundance of systemic microbiota. This ultimately remodels the ITME, improving the therapeutic efficacy of the PD-L1 blocker with a tumor inhibition rate of over 90% and significantly extending the median survival of 4T1 tumor-bearing mice.

Ultrasensitive Optical Detection and Elimination of Residual Microtumors with a Postoperative Implantable Hydrogel Sensor for Preventing Cancer Recurrence.

In vivo optical imaging of trace biomarkers in residual microtumors holds significant promise for cancer prognosis but poses a formidable challenge. Here, a novel hydrogel sensor is designed for ultrasensitive and specific imaging of the elusive biomarker. This hydrogel sensor seamlessly integrates a molecular beacon nanoprobe with fibroblasts, offering both high tissue retention capability and an impressive signal-to-noise ratio for imaging. Signal amplification is accomplished through exonuclease I-mediated biomarker recycling. The resulting hydrogel sensor sensitively detects the biomarker carcinoembryonic antigen with a detection limit of 1.8 pg mL-1 in test tubes. Moreover, it successfully identifies residual cancer nodules with a median diameter of less than 2 mm in mice bearing partially removed primary triple-negative breast carcinomas (4T1). Notably, this hydrogel sensor is proven effective for the sensitive diagnosis of invasive tumors in post-surgical mice with infiltrating 4T1 cells, leveraging the role of fibroblasts in locally enriching tumor cells. Furthermore, the residual microtumor is rapidly photothermal ablation by polydopamine-based nanoprobe under the guidance of visualization, achieving ≈100% suppression of tumor recurrence and lung metastasis. This work offers a promising alternative strategy for visually detecting residual microtumors, potentially enhancing the prognosis of cancer patients following surgical interventions.

Safe engineering of cancer-associated fibroblasts enhances checkpoint blockade immunotherapy.

Abundant cancer-associated fibroblasts (CAFs) in highly fibrotic breast cancer constitute an immunosuppressive barrier for T cell activity and are closely related to the failure of immune checkpoint blockade therapy (ICB). Inspired by the similar antigen-processing capacity of CAFs to professional antigen-presenting cells (APCs), a "turning foes to friends" strategy is proposed by in situ engineering immune-suppressed CAFs into immune-activated APCs for improving response rates of ICB. To achieve safe and specific CAFs engineering in vivo, a thermochromic spatiotemporal photo-controlled gene expression nanosystem was developed by self-assembly of molten eutectic mixture, chitosan andfusion plasmid. After photoactivatable gene expression, CAFs could be engineered as APCs via co-stimulatory molecule (CD86) expression, which effectively induced activation and proliferation of antigen-specific CD8 + T cells. Meanwhile, engineered CAFs could also secrete PD-L1 trap protein in situ for ICB, avoiding potential autoimmune-like disorders caused by "off-target" effects of clinically applied PD-L1 antibody. The study demonstrated that the designed nanosystem could efficiently engineer CAFs, significantly enhance the percentages of CD8+ T cells (4-folds), result in about 85% tumor inhibition rate and 83.3% survival rate at 60 days in highly fibrotic breast cancer, further inducing long-term immune memory effects and effectively inhibiting lung metastasis.