Nutrient-sensing nanoprotoplast augments tumor accumulation and immune response with short-term starvation

Many efforts have been devoted to improve delivery efficiency of nanocarriers in tumor site. However, current strategies are mainly focusing on regulating the materials rather than the biological system. We here demonstrate that short-term starvation (STS) can enhance the cellular uptake and tumor accumulation of nanocarriers. Tumor cells can assimilate a significant amount of extracellular massive necrotic cell debris vesicles (NCDVs) and built more blood vessels after STS treatment. We thereby developed a NCDVs-mimicking nanoprotoplast using bacterial protoplast. This NCDVs-mimicking nanoprotoplast can efficiently accumulate at tumor site and inhibit type 1 or 2 insulin-like growth factor receptor (IGF-1R or IGF-2R, respectively) mediated cell proliferation by reducing IGF-1 with STS treatment and delivering inhibitors. Moreover, this nanoprotoplast can trigger the immune response and be further augmented with STS treatment. Collectively, STS treatment can not only improve the cellular uptake and tumor accumulation of NCDVs-mimicking nanoprotoplast, but also strengthen the antitumor immunity of the nanoprotoplast.