Nanomedicine has emerged as a potent weapon against cancer, yet its therapeutic potential is hampered by limited diffusion within tumor tissues. Cell-penetrating peptides (CPPs), such as the trans-activator of transcription (Tat) peptide, can facilitate interactions between carriers and cells; however, their capacity to penetrate cell layers remains limited. Here, we present evidence that cyclic Tat (cTat) can effectively enhance the penetration of nanoparticles into tumors. Compared with linear Tat, cTat exhibited a 10-fold increase in the dissociation constant (Kd) but a nearly dissociation rate constant (Koff) with the cell membrane. This facilitated easier uptake and penetration of cTat-modified liposomes (cTat-Lip) into tumor cells. In vivo studies corroborated these findings; cTat-Lip demonstrated higher tumor penetration and a more even distribution compared to Tat-Lip. Furthermore, we evaluated the impact of cTat-Lip in mouse tumor models and patient-derived xenograft (PDX) models. We confirmed that after enhancing tumor penetration, DOX-loaded cTat-Lip could modulate the immune microenvironment at the tumor site, increasing the proportion of M1-type macrophages and promoting tumor therapy. These results highlight the substantial impact of two-dimensional structure modification of CPPs like Tat on their targeting affinity, emphasize of reducing the peptide’s targeting affinity to achieve enhanced tumor penetration and improved therapeutic outcomes.

Asparagus cochinchinensis is a member of the Asparagaceae family whose medicinal part is the dried root tuber. The distribution of A. cochinchinensis and its secondary metabolites are closely associated with environmental factors, such as climate and soil properties. By establishing and optimizing a maximum entropy model, we analyzed and predicted the distribution pattern and migration direction of suitable habitats for A. cochinchinensis and determined the main environmental factors affecting the accumulation of secondary metabolites. Under current climatic conditions, the area of suitable habitats for A. cochinchinensis (208.38 × 104 km2) accounts for 21.71% of the land area of China. Under future climate scenarios, the total area of suitable habitats hardly changes. The area of highly suitable habitats significantly decreases under the SSP1-RCP2.6 and SSP3-RCP7 scenarios but eventually increases under the SSP5-RCP8.5 scenario, which indicates that A. cochinchinensis might adapt better to a high-carbon-emissions scenario. Under different climate scenarios, low-impact areas mainly occur in southern China. Highly suitable habitats primarily occur in the southeastern Sichuan Basin, northern Guangxi, eastern Guizhou, and western Hunan. The total contents of saponins and polysaccharides in A. cochinchinensis were significantly, but oppositely, correlated with temperature, precipitation, and other factors. This study has identified environmental factors affecting the growth and quality of A. cochinchinensis, which has guiding significance for resource conservation and site selection for large-scale cultivation.