Development of nanocarriers, which can selectively accumulate and remain within the tumor tissue matrix, is beneficial for non-invasive cancer diagnosis and therapy. In this study, a well-defined pH-sensitive block copolymer, i.e., succinic anhydride (SA)-modified poly(2-diisopropylaminoethyl methacrylate)-block-poly(2aminoethyl methacrylate hydrochloride) (PDPA-b-PAMA/SA), was prepared by a two-step atom transfer radical polymerization (ATRP) and subsequent amidation. The low critical micelle concentration (CMC, 40.7 Â 10 À4 mg mL À1 ) of PDPA-b-PAMA/SA investigated in pH 7.4 aqueous solution confirmed the adequate thermodynamic stability of its self-assembly. In addition, the pH-sensitive aggregation behaviors of blank and drug-loaded PDPA-b-PAMA/SA were systematically studied at typical pH conditions (7.4 and 6.5) using dynamic light scattering (DLS) and transmission electron microscopy (TEM). Compared with the control sample, i.e., poly(D,L-lactide)-block-poly(2-aminoethyl methacrylate hydrochloride (PLA-b-PAMA/ SA), both blank and drug-loaded PDPA-b-PAMA/SA (PDPA-b-PAMA/SA@DOX$HCl) exhibited obvious aggregation through electric interaction between the positive charge of the protonated PDPA block and the negative charge of the PAMA/SA block at tumor sites under slightly acidic condition. Moreover, the drug-loaded nanocarriers exhibited accelerated drug release profiles in response to the acidic condition due to the electric repulsion between the protonated PDPA block and positive DOX$HCl. Cytotoxicity assay results demonstrated that the pH-sensitive block copolymer did not demonstrate obvious cytotoxicity, even at a concentration up to 100 mg mL À1 . The enhanced intracellular DOX$HCl distribution in nuclei was also confirmed by confocal laser scanning microscopy (CLSM). Thus, these results suggest that PDPA-b-PAMA/SA provides a feasible platform for efficient tumor-targeted therapy.

Block polymers are synthesized to prepare nanocarriers with dual pHsensitivity, which are expected to prolong blood circulation time, reduce systemic toxicity, enhance tumor cell uptake and accelerate intracellular drug release for efficient anti-cancer therapy.

Two types of diblock copolymers are synthesized to construct dual pH-responsive micelles with a charge-conversional property for effective drug delivery.

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Using genome-wide data of 89 ancient individuals dated to 5100 to 100 years before the present (B.P.) from 29 sites across the Tibetan Plateau, we found plateau-specific ancestry across plateau populations, with substantial genetic structure indicating high differentiation before 2500 B.P. Northeastern plateau populations rapidly showed admixture associated with millet farmers by 4700 B.P. in the Gonghe Basin. High genetic similarity on the southern and southwestern plateau showed population expansion along the Yarlung Tsangpo River since 3400 years ago. Central and southeastern plateau populations revealed extensive genetic admixture within the plateau historically, with substantial ancestry related to that found in southern and southwestern plateau populations. Over the past ~700 years, substantial gene flow from lowland East Asia further shaped the genetic landscape of present-day plateau populations. The high-altitude adaptive EPAS1 allele was found in plateau populations as early as in a 5100-year-old individual and showed a sharp increase over the past 2800 years.

The extreme environments of the Tibetan Plateau offer considerable challenges to human survival, demanding novel adaptations. While the role of biological and agricultural adaptations in enabling early human colonization of the plateau has been widely discussed, the contribution of pastoralism is less well understood, especially the dairy pastoralism that has historically been central to Tibetan diets. Here, we analyze ancient proteins from the dental calculus ( n  = 40) of all human individuals with sufficient calculus preservation from the interior plateau. Our paleoproteomic results demonstrate that dairy pastoralism began on the highland plateau by ~3500 years ago. Patterns of milk protein recovery point to the importance of dairy for individuals who lived in agriculturally poor regions above 3700 m above sea level. Our study suggests that dairy was a critical cultural adaptation that supported expansion of early pastoralists into the region’s vast, non-arable highlands, opening the Tibetan Plateau up to widespread, permanent human occupation.

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