Innovative Nanomedicine Delivery: Targeting Tumor Microenvironment to Defeat Drug Resistance

Abstract

Nanodrug delivery systems have revolutionized tumor therapy like never before. By overcoming the complexity of the tumor microenvironment (TME) and bypassing drug resistance mechanisms, nanotechnology has shown great potential to improve drug efficacy and reduce toxic side effects. This review examines the impact of the TME on drug resistance and recent advances in nanomedicine delivery systems to overcome this challenge. Characteristics of the TME such as hypoxia, acidity, and high interstitial pressure significantly reduce the effectiveness of chemotherapy and radiotherapy, leading to increased drug resistance in tumor cells. Then, this review summarizes innovative nanocarrier designs for these microenvironmental features, including hypoxia-sensitive nanoparticles, pH-responsive carriers, and multifunctional nanosystems that enable targeted drug release and improved drug penetration and accumulation in tumors. By combining nanotechnology with therapeutic strategies, this review offers a novel perspective by focusing on the innovative design of nanocarriers that interact with the TME, a dimension often overlooked in similar reviews. We highlight the dual role of these nanocarriers in therapeutic delivery and TME modulation, emphasize their potential to overcome drug resistance, and look at future research directions.

Keywords: drug resistance; nanomedicine delivery; tumor microenvironment.

Figure 1

Composition of the TME. The TME consists of a variety of cellular and non-cellular components, including tumor-associated fibroblasts (CAFs); immune cells such as macrophages, T cells, natural killer cells, and endothelial cells; pericytes; the extracellular matrix (ECM); and growth factors and cytokines. Created with BioRender.com.

Figure 2

Schematic diagram of nanomaterials employed to diagnose and treat cancers, including nanodiamonds, mesoporous silica, metal nanoparticles (MNPs), liposomes, quantum dots (QDs), polymeric NPs, micelles, and dendrimers. Created with BioRender.com.

Figure 3

The p-nitrobenzyl groups in mPEG-PLG-NC are supposed to be reduced to p-aminobenzyl groups by overexpressed nitroreductase in hypoxic cells and undergo spontaneous fragmentation via 1,6-elimination, resulting in hypoxiaresponsive drug release. (Reprinted with permission from [58]. Copyright 2020 American Chemical Society).

Figure 4

Acidic pH-responsive poly(lactide-co-glycolide) (PLGA) nanoparticles for the endo-lysosome-specific release of 522, a novel TLR7/8 agonist. Bicarbonate salt was incorporated into the new formulation to generate carbon dioxide (CO₂) gas at acidic pH, which can disrupt the polymer shell to rapidly release the payload, and the polymer shell can be used for the release of the payload. (Reprinted with permission from [71]. Copyright 2018 Royal Society of Chemistry).

Figure 5

Nanocarrier strategies to overcome tumor drug resistance. Tumor drug resistance mediated by ATP-binding cassette (ABC) transporters is addressed through two strategies: reversal and bypass. Traditional chemotherapy drugs are effluxed by ABC transporters, reducing efficacy (top left). Reversal involves nanocarriers co-delivering drugs and transporter inhibitors to block efflux and restore drug sensitivity (top right). The bypass strategy uses drug-encapsulated nanoparticles to avoid transporter recognition, enabling intracellular drug release after uptake (bottom right), improving efficacy compared to unencapsulated drugs (bottom left). Created with BioRender.com.

Figure 6

Mechanism of pH-responsive polymer nanomaterials for tumor-targeted drug delivery. Anti-tumor drugs are encapsulated into pH-responsive polymer nanomaterials through a drug-loading process. In normal tissues (pH = 7.4), the nanomaterials remain stable, minimizing premature drug release. Upon reaching the acidic tumor microenvironment (pH < 6.5), the pH-responsive polymers degrade, triggering the controlled release of the encapsulated drugs. This mechanism enhances drug delivery efficiency to tumor cells while reducing off-target effects in normal tissues. Created with BioRender.com.