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How to break through the poor response of current drug therapy, which often resulted from tumor microenvironment heterogeneity (TMH), remains an enormous challenge in the treatment of critical diseases. In this work, a practical solution on bio‐responsive dual‐drug conjugates for overcoming TMH and improving antitumor treatment, which integrates the advantages of macromolecular drugs and small‐molecular drugs, is proposed. Nanoparticulate prodrugs based on small‐molecular drug and macromolecular drug conjugates are designed as a robust weapon for programmable multidrug delivery at tumor‐specific sites: the tumor microenvironment acid condition triggers delivery of macromolecular aptamer drugs (AX102) to manage TMH (including tumor stroma matrix, interstitial fluid pressure, vasculature network, blood perfusion, and oxygen distribution), and intracellular lysosomal acid condition activates rapid release of small‐molecular drugs (doxorubicin and dactolisib) to enhance curative effects. As compared with doxorubicin chemotherapy, the tumor growth inhibition rate is enhanced by 47.94% after multiple tumor heterogeneity management. This work verifies that the nanoparticulate prodrugs facilitate TMH management and therapeutic response enhancements, as well as elucidates synergetic mechanisms for drug resistance reversal and metastasis inhibition. It is hoped that the nanoparticulate prodrugs will be an excellent demonstration of the co‐delivery of small‐molecular drugs and macromolecular drugs.

Protein-based drugs have been demonstrating great potential on the treatment of various diseases, but most of them encounter many difficulties in clinical trials or uses, such as instability, low bioavailability,...

Synthesizing biomimetic systems with stereospecific architectures and advanced bioactivity remains an enormous challenge in modern science. To fundamentally eliminate biosafety issues of natural oncolytic viruses, the development of synthetic virus-inspired particles with high oncolytic activity is urgently needed for clinical antitumor treatments. Here, we describe the design and synthesis of enantiomeric virus-inspired particles for efficient oncolytic therapy from homochiral building blocks to stereospecific supramolecular constructions. The L-virus-inspired oncolytic particles (L-VOPs) and D-VOPs possess similar biomimetic nanostructures but mirror-imaged enantiomeric forms. It is important that both L-VOPs and D-VOPs successfully mimic the pharmacological activity of oncolytic viruses, including direct tumor lysis and antitumor immune activation. D-VOPs provide quite better oncolytic efficacy than that of clinical-grade oncolytic agents (LTX-315, IC50 = 53.00 μg mL–1) with more than 5-fold decrease in IC50 value (10.93 μg mL–1) and close to 100% tumor suppression (98.79%) against 4T1 tumor-bearing mice, attributed to the chirality-dependent tumor recognition, interaction, antidegradation, and immunotherapy. This work provides a strategy for the synthesis of stereospecific biomimetic material systems as well as develops an advanced candidate for biomimetic oncolytic agents without biosafety risks.