Smart biomimetic “nano-med-fireman” blocking inflammation and lactate metabolism crosstalk for normalized spatiotemporal photo-immunotherapy

The immense complexity and interconnectedness of inflammation and metabolism in the primary tumor ecosystem and pre-metastatic niches (PMN) present an enormous challenge for developing advanced nano-medicines for cancer immunotherapy. Herein, an intelligent tumor- and PMN-tropic bioactive "nano-med-fireman" (PsiL@M1M) was developed to not only arouse an appropriate photothermal immune cascade but also to "extinguish" the accompanying excessive inflammation. Ultimately, it aims to revitalize the immunosuppressive tumor microenvironment (TME) to spatiotemporally and effectively inhibit tumor metastasis and recurrence. PsiL@M1M was devised by incorporating the siRNA of lactate dehydrogenase A (siLDHA) on the functionalized photothermal mesoporous polydopamine (mPDA) and coupled with an M1-type macrophage membrane (M1M) to enable the capacity of inflammation targeting and modulation. PsiL@M1M actively accumulated and destroyed the primary tumor via photothermal therapy and subsequently mitigated the photothermal therapy-induced inflammatory cascade (e.g., epithelial mesenchymal transition) via cytokine neutralization, eliminating the supply of tumor-derived secretory factors as "nutrients" for PMN. Concurrently, siLDHA interfered with lactate (LA) production, inhibited inflammation-LA communication and relieved immune checkpoint, thus profoundly reversing the immunosuppressive microenvironment of both the primary tumor and PMN. Through cooperation, PsiL@M1M initiated normalized hypo-inflammatory photo-immunotherapy against both local tumor growth and spontaneous metastasis/recurrence. Our study provides a paradigm for a new generation of photothermal nano-medicines for the whole process of tumor treatment.