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Cell membrane-camouflaged nanoparticles for cancer therapy have received a burgeoning interest over the past years. However, the low drug loading and intratumoral release efficiency, and lack of precise targeting remains a big challenge; in addition, foreign carriers used may pose an expected burden in the course of metabolism. In this study, we designed and fabricated a novel NIR-responsive highly targeted carrier-free nanosystem by coating the exactly identical source of cracked cancer cell membranes (CCCMs) specifically derived from the homologous tumors onto the surface of the co-assembly nanoparticles of doxorubicin (DOX) and FDA-approved photothermal agent, indocyanine green (ICG). The nanosystems exhibited a high drug loading capacity (89.8%), cancer cell self-recognized ability and immune escape function. Further, the nanodrugs could be efficiently released for the membrane disturbance triggered by photothermal effect of ICG under NIR irradiation. The tumor-bearing mice model demonstrated that the self-carried DOX NPs@ICG@CCCM nanoparticles possessed a strong synergistic chemo-/photothermal therapeutic efficacy against tumors in vivo. The present strategy could be developed as a universal approach for designing and constructing carrier-free theranostic nanovehicles by intentionally selecting specific cancer cell membrane and the inner loading cargoes.

Myocardial infarction (MI) leads to the mass death of cardiomyocytes accompanying with the unfavorable alternation of microenvironment, a fibrosis scar deprived of electrical communications, and the lack of blood supply in the infarcted myocardium. The three factors are inextricably intertwined and thus result in a conservative MI therapy efficacy in clinic. A holistic approach pertinently targeted to these three key points would be favorable to rebuild the heart functions. Here, an injectable conductive hydrogel was constructed via in situ Michael addition reaction between multi-armed conductive crosslinker tetraaniline-polyethylene glycol diacrylate (TA-PEG) and thiolated hyaluronic acid (HA-SH). The resultant soft conductive hydrogel with equivalent myocardial conductivity and anti-fatigue performance was loaded with plasmid DNA encoding eNOs (endothelial nitric oxide synthase) nanocomplexes and adipose derived stem cells (ADSCs) for treating MI. The TA-PEG/HA-SH/ADSCs/Gene hydrogel-based holistic system was injected into the infarcted myocardium of SD rats. We demonstrated an increased expression of eNOs in myocardial tissue the heightening of nitrite concentration, accompanied with upregulation of proangiogenic growth factors and myocardium related mRNA. The results of electrocardiography, cardiogram, and histological analysis convincingly revealed a distinct increase of ejection fraction (EF), shortened QRS interval, smaller infarction size, less fibrosis area, and higher vessel density, indicating a significant improvement of heart functions. This conception of combination approach by a conductive injectable hydrogel loaded with stem cells and gene-encoding eNOs nanoparticles will become a robust therapeutic strategy for the treatment of MI.

Introducing drugs into gene delivery systems to fabricate co-delivery systems for synergy therapy has become a promising strategy for tumor therapy. In this study, a dual responsive co-delivery system RHD/p53 was fabricated to enhance the antitumor efficacy with a low dose of doxorubicin (DOX). The reducible branched cationic polypeptide (RBCP), which was cross-linked via the thiol groups of two three-armed cationic peptides (CRR)2KRRC and (CHH)2KHHC, was designated as RH. Then, DOX was immobilized on RH via pH-sensitive hydrazone bonds to obtain RHD. The positively charged RHD could compress p53 plasmid to form RHD/p53 complexes. After RHD/p53 complexes accumulated in tumor sites, the ability of cell penetrating by cationic peptide (CRR)2KRRC would facilitate the cellular internalization of complexes. Then, the complexes would be trapped in endosome, and the cleavage of hydrazone bonds in the intracellular acidic endosome could lead to pH-induced release of DOX. Additionally, the ability of protonation by (CHH)2KHHC could promote the escape of complexes from endosome to cytoplasm. Due to the cleavage of disulfide bonds triggered by the high-content GSH in cytoplasm, the complexes would be degraded and released p53 for co-therapy to improve antitumor efficacy. Both in vitro and in vivo studies indicated that dual responsive co-delivery system RHD/p53 could enhance antitumor efficacy, which provides a useful strategy for co-delivery of different therapeutic agents in tumor treatment.

To improve the tumor therapeutic efficiency and reduce undesirable side effects, ternary FK/p53/PEG-PLL(DA) complexes with a detachable surface shielding layer were designed. The FK/p53/PEG-PLL(DA) complexes were fabricated by coating the folate incorporated positively charged FK/p53 complexes with charge-switchable PEG-shield (PEG-PLL(DA)) through electrostatic interaction. At the physiological pH 7.4 in the bloodstream, PEG-PLL(DA) could extend the circulating time by shielding the positively charged FK/p53 complexes. After the accumulation of the FK/p53/PEG-PLL(DA) complexes in tumor sites, tumor-acidity-triggered charge switch led to the detachment of PEG-PLL(DA) from the FK/p53 complexes, and resulted in efficient tumor cell entry by folate-mediated uptake and electrostatic attraction. Stimulated by the high content glutathione (GSH) in cytoplasm, the cleavage of disulfide bond resulted in the liberation of proapoptosis peptide C-KLA(TPP) and the p53 gene, which exerted the combined tumor therapy by regulating both intrinsic and extrinsic apoptotic pathways. Both in vitro and in vivo studies confirmed that the ternary detachable complexes FK/p53/PEG-PLL(DA) could enhance antitumor efficacy and reduce adverse effects to normal cells. These findings indicate that the tumor-triggered decomplexation of FK/p53/PEG-PLL(DA) supplies a useful strategy for targeting delivery of different therapeutic agents in synergetic anticancer therapy.

The present study reported a lysosome-acidity-targeting bio-responsive nanovehicle self-assembled from dextran (Dex) and phenylboronic acid modified cholesterol (Chol-PBA), aiming at the nucleus-tropic drug delivery. The prominent advantage of this assembled nanoconstruction arose from its susceptibility to acidity-labile dissociation concurrently accompanied with the fast liberation of encapsulated drugs, leading to efficient nuclear drug translocation and consequently favorable drug efficacy. By elaborately exploiting NH4Cl pretreatment to interfere with the cellular endosomal acidification progression, this study clearly evidenced at a cellular level the strong lysosomal-acidity dependency of nuclear drug uptake efficiency, which was shown to be the main factor influencing the drug efficacy. The boronate-linked nanoassembly displayed nearly no cytotoxicity and can remain structural stability under the simulated physiological conditions including 10% serum and the normal blood sugar concentration. The cellular exposure to cholesterol was found to bate the cellular uptake of nanoassembly in a dose-dependent manner, suggesting a cholesterol-associated mechanism of the intracellular internalization. The in vivo antitumor assessment in xenograft mouse models revealed the significant superiority of DOX-loaded Dex/Chol-PBA nanoassembly over the controls including free DOX and the DOX-loaded non-sensitive Dex-Chol, as reflected by the more effective tumor-growth inhibition and the better systematic safety. In terms of the convenient preparation, sensitive response to lysosomal acidity and efficient nuclear drug translocation, Dex/Chol-PBA nanoassembly derived from natural materials shows promising potentials as the nanovehicle for nucleus-tropic drug delivery especially for antitumor agents. More attractively, this study offers a deeper insight into the mechanism concerning the contribution of acidity-responsive delivery to the enhanced chemotherapy performance.