Nanoparticles camouflaged by red blood cell (RBC) membranes have attracted considerable attention owing to reservation of structure of membrane and surface proteins, endowing prominent cell-specific function including biocompatibility, prolonged circulation lifetime, and reduced reticular endothelial system (RES) uptake ability. Considering the drawbacks of carrier-free nanomedicine including the serious drug burst release, poor stability, and lack of immune escape function, herein we developed and fabricated a novel RBC membranes biomimetic combinational therapeutic system by enveloping the small molecular drug coassemblies of 10-hydroxycamptothecin (10-HCPT) and indocyanine green (ICG) in the RBC membranes for prolonged circulation, controlled drug release, and synergistic chemo-photothermal therapy (PTT). The self-reorganized RBCs@ICG-HCPT nanoparticles (NPs) exhibited a diameter of ∼150 nm with core–shell structure, high drug payload (∼92 wt %), and reduced RES uptake function. Taking advantage of the stealth functionality of RBC membranes, RBCs@ICG-HCPT NPs remarkably enhanced the accumulation at the tumor sites by passive targeting followed by cellular endocytosis. Upon the stimuli of near-infrared laser followed by acidic stimulation, RBCs@ICG-HCPT NPs showed exceptional instability by heat-mediated membrane disruption and pH change, thereby triggering the rapid disassembly and accelerated drug release. Consequently, compared with individual treatment, RBCs@ICG-HCPT NPs under dual-stimuli accomplished highly efficient apoptosis in cancer cells and remarkable ablation of tumors by chemo-PTT. This biomimetic nanoplatform based on carrier-free, small molecular drug coassemblies integrating imaging capacity as a promising theranostic system provides potential for cancer diagnosis and combinational therapy.

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Positive resection margin frequently exists in breast‐conserving treatment (BCT) of early‐stage breast cancer, and insufficient therapeutic efficacy is common during radiotherapy (RT) in advanced breast cancer patients. Moreover, a multimodal nanotherapy platform is urgently required for precision cancer medicine. Therefore, a biodegradable cyclic RGD pentapeptide/hollow virus‐like gadolinium (Gd)‐based indocyanine green (R&HV‐Gd@ICG) nanoprobe is developed to improve fluorescence image‐guided surgery and breast cancer RT efficacy. R&HV‐Gd exhibits remarkably improved aqueous stability, tumor retention, and target specificity of ICG, and achieves outstanding magnetic resonance/second near‐infrared (NIR‐II) window multimodal imaging in vivo. The nanoprobe‐based NIR‐II fluorescence image guidance facilitates complete tumor resection, improves the overall mouse survival rate, and effectively discriminates between benign and malignant breast tissues in spontaneous breast cancer transgenic mice (area under the curve = 0.978; 95% confidence interval: 0.952, 1.0). Moreover, introducing the nanoprobe to tumors generated more reactive oxygen species under X‐ray irradiation, improved RT sensitivity, and reduced mouse tumor progression. Notably, the nanoprobe is biodegradable in vivo and exhibits accelerated bodily clearance, which is expected to reduce the potential long‐term inorganic nanoparticle toxicity. Overall, the nanoprobe provides a basis for developing precision breast cancer treatment strategies.

Locating nanomedicines at the active sites plays a pivotal role in the nanoparticle-based cancer therapy field. Herein, a multifunctional nanotherapeutic is designed by using graphene oxide (GO) nanosheets with rich carboxyl groups as the supporter for hyaluronic acid (HA)–methotrexate (MTX) prodrug modification via an adipicdihydrazide cross-linker, achieving synergistic multistage tumor-targeting and combined chemo-photothermal therapy. As a tumor-targeting biomaterial, HA can increase affinity of the nanocarrier toward CD44 receptor for enhanced cellular uptake. MTX, a chemotherapeutic agent, can also serve as a tumor-targeting enhancer toward folate receptor based on its similar structure with folic acid. The prepared nanosystems possess a sheet shape with a dynamic size of approximately 200 nm and pH-responsive drug release. Unexpectedly, the physiological stability of HA–MTX prodrug-decorated GO nanosystems in PBS, serum, and even plasma is more excellent than that of HA-decorated GO nanosystems, while both of them exhibit an enhanced photothermal effect than GO nanosheets. More importantly, because of good blood compatibility as well as reduced undesired interactions with blood components, HA–MTX prodrug-decorated GO nanosystems exhibited remarkably superior accumulation at the tumor sites by passive and active targeting mechanisms, achieving highly effective synergistic chemo-photothermal therapeutic effect upon near-infrared laser irradiation, efficient ablation of tumors, and negligible systemic toxicity. Hence, the HA–MTX prodrug-decorated hybrid nanosystems have a promising potential for synergistic multistage tumor-targeting therapy.

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The clinical translation of methotrexate (MTX) is limited because of low aqueous solubility, poor bioavailability, low uptake efficiency, and toxicity concerns. Herein, dual-acting MTX (not only targeting folate receptors but also killing cells via inhibition of intracellular folate metabolism) and hyaluronic acid (HA, targeting CD44 receptors) were selected to be covalently linked by the redox-responsive disulfide bond. The synthesized prodrug (HA–SS–MTX) as a molecular structural motif could self-assemble into simple yet multifunctional nanoparticles (HA–SS–MTX NPs) in aqueous solution. The HA–SS–MTX NPs displayed an average diameter of ∼110 nm with a uniformly spherical shape and maintained stability in different physiological media. Moreover, the HA–SS–MTX NPs could exhibit a sharp redox-dependent response for rapid structure disassembly and sequential MTX release compared to the redox-irresponsive group (HA–ADH–MTX NPs). Furthermore, the results of confocal microscopy and flow cytometry verified that the nanosystems were selectively uptaken by cancer cells via folate and CD44 receptor-mediated internalization through the dual-active targeting mechanism. In addition, HA–SS–MTX NPs could accumulate within tumor sites for a longer period. Notably, in vitro and in vivo antitumor results demonstrated that HA–SS–MTX NPs significantly promoted the death of cancer cells and enhanced the inhibition of tumor growth while reducing the toxicity as compared to MTX and HA–ADH–MTX NPs. Therefore, the smart HA–SS–MTX NPs as the simple and efficient platform have great potential in tumor-targeting drug delivery and therapy.

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The “Watson–Crick G≡C”-inspired carrier-free nanodrug have excellent tumor microenvironment-triggered active self-targeting ability and enhanced synergistic chemotherapeutic effects.