Hybrid nanoparticles prolong the circulation time, improve the accumulation at the tumor, and antitumor efficacy of loading cargoes. (a) The plasma pharmacokinetic profiles of LTX‐315 by intravenous administration of free LTX‐315 and LTX‐315 loaded NPs. (b) Fluorescent images of mice and major organs were collected from mice injected with hybrid NPs conjugated with cRGD (targeted NPs) or nontargeted NPs co‐entrapping LTX‐315 and Cyanine 5.5‐labeled siRNA. (c) Quantification of fluorescence intensities of targeted NPs and nontargeted NPs in tumors and organs of treated mice. Data were represented as mean ± SD (n = 3). Two‐tailed Student's t‐test, *p < 0.05. (d) Tumor volumes of mice treated with PBS (control), LTX‐NPs, siR‐NPs, and LTX/siR‐NPs with increasing time. Data were represented as mean ± SD (n = 5), two‐way ANOVA with Tukey's multiple comparison test of tumor sizes at Day 15, ***p < 0.001. (e) Tumor weight, (f) images of isolated tumors, and (g) histological analysis of tumors collected from treated mice. Data represented as mean ± SD (n = 5). One‐way ANOVA with Tukey's multiple comparison test, **p < 0.01; ***p < 0.001