No abstract

Photodynamic therapy (PDT) is clinically promising in destructing primary tumors but ineffective against distant metastases. This study reports the use of immunogenic nanoparticles mediated combination of PDT and magnetic hyperthermia to synergistically augment the anti‐metastatic efficacy of immunotherapy. Janus nanobullets integrating chlorine e6 (Ce6) loaded, disulfide‐bridged mesoporous organosilica bodies with magnetic heads (M‐MONs@Ce6) are tailored for redox/pH‐triggered photosensitizer release accompanying their matrix degradation. Cancer cell membrane cloaking enables favorable tumor‐targeted accumulation and prolonged blood circulation time of M‐MONs@Ce6. The combination of PDT and magnetic hyperthermia has a strong synergy anticancer activity and simultaneously elicits a sequence of immunogenic cell death, resulting in synergistically tumor‐specific immune responses. When combined with anti‐CTLA‐4 antibody, the biomimetic and biodegradable nanoparticle enables the notable eradication of primary and deeply metastatic tumors with low systematic toxicity, thus potentially advancing the development of combined hyperthermia, PDT, and checkpoint blockade immunotherapy to combat cancer metastasis.

chemotherapy while reducing drug doses and toxicity. [2] The killing of tumor cells by chemotherapeutics such as anthracyclines, taxanes, mitoxantrone, and oxaliplatin elicits innate and adaptive immune responses by immunogenic cell death (ICD). In ICD, the release of tumorassociated antigens, damage-associated molecular patterns, and pro-inflammatory cytokines leads to recruitment and activation of immune effector cells such as tumor-specific T cells. [3] This vaccine-like effect of ICD can convert an immunosuppressive tumor microenvironment (TME) to an immunogenic one that responds better to treatment with immune checkpoint blockades and adjuvants. [4] Chemoimmunotherapy has proven effective in inhibiting the development and progression of solid tumors and distant metastases in preclinical studies and clinical trials. However, many patients suffer from immune-related adverse events due to off-target toxicity. [5] To reduce this toxicity and improve the therapeutic response, drug carriers have been designed to allow on-demand drug release at tumor sites. Chemotherapy causes off-target toxicity and is often ineffective against solid tumors. Targeted and on-demand release of chemotherapeutics remains a challenge. Here, cancer-cell-membrane-coated mesoporous organosilica nanoparticles (MONs) containing X-ray-and reactive oxygen species (ROS)responsive diselenide bonds for controlled release of doxorubicin (DOX) at tumor sites are developed. DOX-loaded MONs coated with 4T1 breast cancer cell membranes (CM@MON@DOX) show greater accumulation at tumor sites and prolonged blood circulation time versus an uncoated control in mice bearing 4T1 orthotopic mammary tumors. Under low-dose X-ray radiation, the DOX-loaded MONs exhibit carrier degradation-controlled release via cleavage of diselenide bonds, resulting in DOX-mediated immunogenic cell death at the tumor site. Combination with a PD-L1 checkpoint blockade further enhances inhibition of tumor growth and metastasis with low systemic toxicity. Together, the findings show the promise of these biomimetic, radiationresponsive diselenide-bond-bridged MONs in chemo-immunotherapy. Chemotherapy is limited by off-target toxicity and ineffectiveness against solid tumors and distant metastases. [1] Chemo-immunotherapy-the combination of chemotherapy and immunotherapy-can improve the effectiveness of The ORCID identification number(s) for the author(s) of this article can be found under