Self-Propelled Gemini-like LMWH-Scaffold Nanodrugs for Overall Tumor Microenvironment Manipulation via Macrophage Reprogramming and Vessel Normalization

Angiogenesis is the hallmark of melanoma that nurtures the tumor microenvironment (TME) for rapid tumor progression. Vessel normalization could benefit melanoma treatment through TME reconstruction, while its limited duration and extent are still the drag. Herein, two kinds of look-like nanodrugs, called Gemini-like nanodrugs (GLnano), were constructed separately with the same scaffold of antiangiogenic low molecular weight heparin (LMWH) and mixed upon administration in vivo. For one, doxorubicin (DOX) was encapsulated into LMWH-chrysin nanodrug (LCY) with DSPE-PEG-anisamide decoration (D-LCA nanodrugs) for active targeting and direct cell killing toward melanoma cells. For another, matrix metalloproteinases (MMPs)-sensitive peptide was conjugated to LMVVH to encapsulate celecoxib (Cel) (C-Lpep nanodrugs), disassembling in TME by MMPs and releasing Cel for M2-to-M1 reprogramming of tumor-associated macrophages. Our results showed that GLnano could remarkably elongate the vessel normalization window up to 12 days with the highest pericyte coverage of nearly 75%, compared to only 4 days by LCY monotherapy. Furthermore, GLnano could spontaneously form the "treatment-delivery" loop to promote nanodrugs toward deep tumor regions, leading to a potent tumor inhibition, metastasis prevention, and overall TME improvements.