Multifunctional Nanoparticles to Over Come ABC Transporter-Mediated Drug Resistance in Cancer: A Short Review

Multifunctional Nanoparticles to Over Come ABC Transporter-Mediated Drug Resistance in Cancer: A Short Review

Samra Ishtiaque Department of Bioengineering Integral University

Lucknow, India

Suhail Ahmad

Department of Bioengineering

Integral University Lucknow, India

Alvina Farooqui Department of Bioengineering Integral University

Lucknow, India

Mohammed Haris Siddiqui Department of Bioengineering Integral University

Lucknow, India

Soban Ahmad Faridi* Department of Bioengineering Integral University

Lucknow, India soban@iul.ac.in

AbstractMultidrug resistance mediated by ATP-binding cassette transporters remains a critical barrier to effective cancer chemotherapy, driving tumor recurrence and treatment failure. This review comprehensively examines innovative multifunctional nanoparticle strategies designed to overcome transporter-mediated efflux mechanisms. We analyze nanocarrier platforms enabling targeted co-delivery of chemotherapeutics with transporter inhibitors, gene-silencing approaches suppressing efflux pump expression, and stimuli-responsive systems exploiting tumor microenvironment features. The work highlights emerging technologies including nanobots and AI-designed nanoparticles while addressing translational challenges like protein corona formation and manufacturing scalability. By synthesizing recent advances in nanomedicine, this review provides researchers with critical insights into next-generation approaches for combating drug-resistant cancers through rational nanomaterial engineering.

Keywords nanocarrier systems; nanomedicine; Cancer nanotherapeutics; Multidrug resistance reversal; ABC transporters

1. Introduction

   Cancer remains a formidable global health challenge and a leading cause of mortality worldwide [1]. While chemotherapy is a cornerstone of systemic cancer treatment, its efficacy is frequently undermined by the development of multidrug resistance (MDR), a phenomenon where cancer cells become simultaneously insensitive to a broad spectrum of structurally and functionally distinct anticancer drugs [2]. MDR is a primary factor in the failure of many chemotherapeutic regimens, leading to tumor recurrence and patient relapse. A principal mechanism responsible for mediating this resistance is the overexpression of ATP-binding cassette (ABC) transporters in cancer cells [3], [4]. These membrane-bound proteins function as energy-dependent efflux pumps, actively expelling a wide range of chemotherapeutic agents from the intracellular environment, thereby reducing their cytosolic

   concentration and preventing them from reaching their therapeutic targets [5].

   Overcoming ABC transporter-mediated MDR is therefore a critical objective in oncology research. Traditional approaches, such as the co-administration of small-molecule inhibitors of ABC transporters, have been met with limited success, often due to systemic toxicity and unfavorable pharmacokinetic profiles [6]. In recent years, the convergence of nanotechnology and medicine has offered a paradigm-shifting approach to address this challenge. Multifunctional nanoparticles have emerged as a highly promising platform for circumventing MDR, owing to their unique physicochemical properties and their capacity for sophisticated molecular engineering [7]. These nanoscale delivery systems can be designed to encapsulate therapeutic payloads, protecting them from premature degradation and recognition by efflux pumps. Furthermore, their surfaces can be modified with targeting ligands for specific delivery to tumor cells and with agents that can actively inhibit ABC transporter function or deplete the cellular energy required for drug efflux.

   This review aims to provide a comprehensive and critical analysis of the state-of-the-art strategies employing multifunctional nanoparticles to overcome ABC transporter- mediated drug resistance in cancer. We will systematically survey the various types of nanocarriers investigated, including liposomes, polymeric nanoparticles, and inorganic nanoparticles, and detail the diverse mechanisms through which they bypass or suppress efflux pump activity. The discussion will encompass passive and active targeting strategies, co- delivery of chemotherapeutics with ABC transporter inhibitors, and innovative approaches designed to modulate the tumor microenvironment to enhance drug efficacy.

   The significance of this review lies in its synthesis of recent advancements in a rapidly evolving and clinically significant

   field. By elucidating the design principles, mechanisms of action, and therapeutic potential of multifunctional nanoparticles, we aim to provide a valuable resource for researchers in oncology, pharmacology, and materials science. Ultimately, a deeper understanding of these sophisticated nanomedical strategies will be instrumental in guiding the rational design of next-generation therapies capable of conquering drug resistance and improving clinical outcomes for cancer patients.

2. ABC Transporters: Mechanisms and

   Therapeutic Challenges

   The ATP-binding cassette (ABC) transporter superfamily represents one of the largest families of transmembrane proteins, playing indispensable roles in cellular homeostasis by facilitating the transport of a vast array of substrates across biological membranes [8]. While essential for physiological processes, a subset of these transporters, notably P-glycoprotein (P-gp, or ABCB1), breast cancer resistance protein (BCRP, or ABCG2), and multidrug resistance-associated protein 1 (MRP1, or ABCC1), are key drivers of multidrug resistance (MDR) in oncology [9], [10], [11]. Their ability to recognize and actively extrude a wide spectrum of chemotherapeutic agents from cancer cells constitutes a formidable barrier to effective treatment. Understanding the intricate structural mechanics of these efflux pumps and the historical context of

   their therapeutic inhibition is crucial for developing strategies to overcome the clinical challenge of MDR.

   The clinical relevance and complexity of this superfamily are underscored by the sheer number of transporters implicated in cancer resistance, the broad range of affected malignancies, and the extensive list of chemotherapeutic drugs they can expel, as detailed in Table 1. Beyond the well-studied P-gp, BCRP, and MRP1, other members of the ABCB, ABCC, and ABCG subfamilies are also significantly involved in conferring drug resistance across various cancer types. For example, MRP2 (ABCC2) contributes to resistance in hepatocellular carcinoma [12], while MRP7 (ABCC10) has been shown to transport taxanes, implicating it in resistance in ovarian and breast cancers [13], [14]. Table 1 illustrates a critical challenge for clinicians: a single tumor type, such as breast cancer, can co- express multiple distinct efflux pumps (e.g., P-gp, BCRP, MRP1), creating a redundant and highly robust resistance network [13]. Furthermore, the substrate polyspecificity is extensive; a single drug like doxorubicin is a substrate for at least P-gp and MRP1 [15], while a single transporter like P-gp can efflux a chemically diverse arsenal of drugs including taxanes, vinca alkaloids, and anthracyclines [16], [17]. This vast functional overlap and redundancy highlight the inherent limitations of targeting a single transporter and form the rationale for developing strategies that can circumvent these efflux mechanisms altogether.

   TABLE I. Clinically Relevant Major ABC Transporters, Associated Malignancies, and Chemotherapeutic Substrates.

   Nanocarrier Design Strategies to

   Circumvent Efflux Pumps

   In response to the clinical shortcomings of small- molecule inhibitors, nanomedicine has introduced a suite of sophisticated strategies designed to fundamentally circumvent ABC transporter-mediated efflux. By encapsulating therapeutic agents within a nanoscale carrier, the drug's interaction with efflux pumps at the cell membrane can be minimized or altogether avoided. Nanoparticles primarily enter cells via endocytic pathways, a mechanism that bypasses the membrane-localized pumps. Once internalized, the nanocarrier releases its high-concentration payload directly into the cytoplasm, effectively overwhelming any remaining efflux capacity and ensuring the drug reaches its intracellular target. This section will explore the key multifunctional nanocarrier designs that leverage this principle, including the co-delivery of inhibitors, gene-silencing approaches, and stimuli-responsive systems.

   A highly promising strategy involves the co-delivery of a chemotherapeutic agent and an ABC transporter inhibitor within a single nanocarrier system. This approach overcomes a major limitation of free-drug co-administration: the divergent pharmacokinetic and biodistribution profiles that prevent both agents from reaching the tumor in the optimal synergistic ratio. For instance, polymeric nanoparticles have been successfully engineered to co-encapsulate paclitaxel with sitravatinib, a potent inhibitor of both P-gp and BCRP, demonstrating marked synergy in resistant tumors [56], [57]. Similarly, liposomal formulations co-encapsulating doxorubicin and the third-generation inhibitor tariquidar have been shown to re-sensitize resistant cells more effectively than the administration of free drugs [58]. The primary strength of this approach lies in ensuring the spatiotemporal co-localization of the drug and inhibitor at the tumor site. However, a significant challenge remains in optimizing the drug-inhibitor ratio within the nanoparticle and controlling their respective release kinetics to ensure maximal therapeutic effect without causing off-target toxicity from the inhibitor.

   An even more fundamental approach to disabling efflux pumps involves the use of nanocarriers to deliver gene- silencing therapeutics, such as small interfering RNA (siRNA), to suppress the expression of ABC transporter genes at the mRNA level. This strategy effectively tackles MDR at its source. Cationic platforms like dendrimers and lipid-based nanoparticles have been extensively studied for their ability to complex with and protect anionic siRNA molecules, delivering them to cancer cells to inhibit the translation of key transporter genes like MDR1 (encoding P- gp). For example, studies utilizing siRNA-loaded dendrimers have demonstrated significant downregulation of MDR1 mRNA and a corresponding increase in sensitivity to doxorubicin [59], [60]. Likewise, inorganic systems, such as gold nanoparticle-siRNA conjugates, have been designed for the targeted knockdown of BCRP [61]. While powerful in principle, the clinical translation of siRNA-based therapies faces hurdles, including the enzymatic degradation of siRNA,

   the efficiency of endosomal escape, and the transient nature of the gene knockdown, which may require repeat administrations [62]. Future research must focus on designing more stable and efficient delivery vectors to realize the full potential of this approach.

   Building on these concepts, advanced nanocarrier systems are being engineered to respond to specific triggers within the tumor microenvironment (TME), allowing for site- specific and on-demand drug release. The acidic nature of the TME (pH ~6.5-6.8) compared to healthy tissue (pH 7.4) is a widely exploited trigger. pH-sensitive nanogels and polymers can be designed to remain stable in systemic circulation but swell or disassemble upon protonation in the acidic TME, releasing their encapsulated drug or inhibitor payload precisely at the tumor site [63]. This not only enhances the therapeutic concentration where it is needed most but also minimizes systemic exposure and associated toxicities. The key advantage of stimuli-responsive systems is the gain in therapeutic specificity. The primary limitation, however, is the inherent heterogeneity of the TME; not all tumor regions are uniformly acidic, which could lead to inconsistent drug release [64].

   To achieve an even higher degree of specificity, researchers are designing systems that respond to enzymes that are aberrantly overexpressed in the TME. Enzymes such as matrix metalloproteinases (MMPs), which are crucial for invasion and metastasis, serve as excellent targets. Nanoparticles can be engineered with drug-retaining linkers that are specifically cleaved by MMPs, ensuring that the therapeutic payload is released only in the enzyme-rich tumor vicinity. Other dysregulated metabolic enzymes associated with cancer progression, including certain lipogenic enzymes like fatty acid synthase (FASN) or key players in glycolysis like hexokinase 2 (HK2), also represent potential triggers. Enzymes like hexokinase 2 (HK2), lactate dehydrogenase (LDH), matrix metalloproteinases (MMPs), certain lipogenic enzymes like fatty acid synthase (FASN), glucose-6- phosphate isomerase (GPI), malic enzyme (ME), and isocitrate dehydrogenase (IDH), are also frequently overexpressed in tumors and contribute to cancer development [65]. While directly targeting intracellular enzymes with extracellular nanoparticles is complex, their activity often creates a unique metabolic signature (e.g., high concentrations of lactate or reactive oxygen species) that can be harnessed. The major strength of enzyme-responsive systems is their high biological specificity. However, this approach also faces challenges related to the heterogeneous expression of target enzymes across different tumor types and even within a single tumor mass.

   Therefore, the development of multi-stimuli-responsive systems represents a critical future direction to create more robust and universally effective delivery platforms. By designing nanoparticles that require a dual trigger for activation, for instance, the acidic pH of the TME to prime the nanoparticle and a specific enzyme like MMP to execute drug release, thus a significantly higher level of tumor selectivity can be achieved. This "AND-gate" logic would minimize premature drug release in healthy tissues and concentrate the therapeutic effect at the intended site, representing a more intelligent and tailored approach to circumventing drug resistance.

   Emerging Nanotechnologies and

   Intelligent Systems

   Beyond established nanocarrier designs, the frontier of nanomedicine is rapidly advancing toward "intelligent" systems that exhibit unprecedented levels of autonomy, precision, and adaptability. These next-generation technologies are poised to transform the approach to combating MDR by integrating principles from robotics, cell biology, and artificial intelligence. They represent a paradigm shift from relatively static delivery vehicles to dynamic agents capable of sensing, processing, and responding to complex biological cues in real-time.

   At the forefront of this evolution are nanoscale robots, or nanobots, which offer unparalleled precision in drug delivery. DNA origami, a technique that involves folding long strands of DNA into prescribed 2D and 3D shapes, has emerged as a leading platform for constructing these bots. Researchers have successfully designed DNA origami structures that act as logic-gated containers, remaining in a "locked" state until they recognize and bind to specific cancer biomarkers on the cell surface [66], [67]. This binding event triggers a conformational change, "unlocking" the nanobot to release its payloadsuch as a P-gp inhibitor or a potent chemotoxindirectly at the target cell. While this technology offers exquisite targeting capabilities, significant translational gaps persist, including the high cost of production, potential immunogenicity, and ensuring the structural integrity of these complex bots within the harsh in vivo environment.

   Another innovative strategy employs a "Trojan horse" approach, hijacking the body's own cells to smuggle nanotherapeutics past formidable biological barriers. A compelling example is the use of neutrophils, which have a natural ability to cross the blood-brain barrier (BBB) to reach sites of inflammation. By loading drug-carrying nanoparticles into these immune cells, researchers have created "Trojanbots" capable of delivering therapies to notoriously difficult-to-treat brain tumors like glioblastoma [68]. Once the neutrophils have traversed the BBB, the nanoparticles can be released to target the tumor cells. This bio-inspired strategy is a powerful demonstraion of how to overcome major physiological obstacles. Its primary limitations lie in the efficiency of nanoparticle loading into host cells without impairing their viability and function, and the potential to trigger unwanted inflammatory responses.

   The sheer complexity of designing nanoparticles to navigate biological systems has necessitated the integration of artificial intelligence (AI) and machine learning (ML) into the development pipeline [69], [70]. AI-driven design can rapidly accelerate the optimization process, which is intractably slow using traditional trial-and-error methods [71]. By feeding large datasets from previous experiments into ML algorithms, it is possible to build predictive models that identify the optimal physicochemical properties, such as size, surface charge, and ligand density for a nanoparticle to achieve a specific goal, like enhanced tumor retention or maximal cellular uptake in resistant cells. This data-centric approach enables a more rational and efficient design of nanomedicines. The primary weakness of this field is its current reliance on large, high-quality, and standardized datasets, which are not always available. Future research

   must not only focus on developing more sophisticated algorithms but also on generating the robust experimental data required to train them effectively.

   Preclinical and Clinical Progress

   The translation of multifunctional nanoparticles from conceptual designs to clinical realities is a complex, multi- stage process, yet the field has made substantial preclinical progress and seen foundational successes in clinical applications. The first generation of anticancer

   nanomedicines, such as Doxil® (liposomal doxorubicin) and Abraxane® (albumin-bound paclitaxel), demonstrated the core principle that nanoparticle encapsulation can improve the therapeutic index of chemotherapies [72], [73]. While not specifically designed to overcome MDR, their clinical approval established a crucial precedent and paved the way for more sophisticated systems. Current research, as summarized in Table 2, is focused on a diverse array of next- generation platforms that are explicitly engineered to combat ABC transporter-mediated resistance.

   TABLE II. Selected Preclinical Studies of Nanoparticle Platforms Targeting ABC Transporter-Mediated Drug Resistance.

   Nanoplatform	Cancer Model	Key Outcome	Stage	Reference
   Lipid-saporin nanoparticles (EC16- 1/saporin)	ABCB1-overexpressing SW620/AD300 and ABCG2-overexpressing NCI-H460/MX20 xenografts	Significant tumor growth inhibition in both ABCB1 and ABCG2 resistant models; IC50 reduced to 2.50 ± 0.43 nM vs >50 nM for controls	Preclinical	[74]
   Hyaluronan-grafted nanoparticle clusters (DOX-GAGs)	P-gp-overexpressing human ovarian adenocarcinoma xenograft model	Superior therapeutic effect over free doxorubicin in resistant tumor model; bypassed P-gp-mediated resistance mechanism	Preclinical	[75]
   Polymeric AIEgen/P-gp siRNA nanoparticles (Py- TPE/siRNA@PMP)	SKOV-3/PTX resistant ovarian cancer and patient- derived xenografts (PDX)	Significant tumor growth suppression in subcutaneous, intraperitoneal metastasis, and PDX models; prolonged mouse survival vs controls	Preclinical	[76]
   Hyaluronan-coated superparamagnetic iron oxide NPs (HA-SPIONs)	Drug-resistant human ovarian cancer cells (SKOV-3)	DOX accumulated at higher levels and distributed wider in tumor tissue than free DOX; significant reduction of tumor growth and extended survival	Preclinical	[77]
   PLGA nanoparticles with SC-514 and 3-BPA	Prostate cancer cells with ABC transporter overexpression	Inhibited ATP Binding Cassette protein-mediated drug resistance; 50% reduction in chemotherapy failure	Preclinical	[78]
   Lipid nanoparticle NBF- 006 (GSTP siRNA)	Advanced NSCLC, pancreatic, and colorectal cancer patients	Disease control rate of 59% (19/38) in heavily pre-treated NSCLC patients; durable partial response in 2 patients	Phase I (NCT03819387)	[79], [80]
   Polymeric micelles with paclitaxel (PT-R-Ms)	Solid tumors with P- glycoprotein efflux	7.89-fold enhancement in PTX permeation; 8-fold increase in bioavailability; 42.9% apoptotic cells vs controls	Preclinical	[81]
   Gold NP-siRNA conjugates (HsiRNA@PGD)	SKBR3 xenograft breast tumor model	Concurrent delivery of doxorubicin and HER2 siRNA; selective tumor accumulation with significant HER2 gene suppression	Preclinical	[82]
   Dual-targeted nanoparticles (SSBPEI- DOX@siRNAs)	Ovarian cancer stem cells	Co-delivery of doxorubicin and siRNA cocktails (survivin, Bcl-2, ABCG2 siRNA); synergistic anti-CSC effects with drug resistance reversal	Preclinical	[83]
   pH/ROS cascade- responsive nanoparticles (PLP-NPs)	Multidrug-resistant colon cancer	Downregulated P-glycoprotein production through NQO1 activity; overcame MDR with tumor-specific cytotoxicity in vivo	Preclinical	[84]
   Trimethyl-chitosan coated gold NPs (AuNPs-TMC)	MCF-7 breast cancer cells	86% gene expression knockdown of EGFR; 50% cell viability reduction; complete cellular uptake after 4h	Preclinical	[85]
   Albumin nanoparticles with piperine-paclitaxel (PP@AN)	Multidrug-resistant triple- negative breast cancer	Enhanced PTX sensitivity through P-gp inhibition; significant increase in drug accumulation and P-gp downregulation at 1:2 ratio	Preclinical	[86]
   Polymeric nanoparticle micellar paclitaxel (PM- Pac)	Stage III-IV high-grade serous ovarian cancer patients	Improved progression-free survival: median 35.5 vs 28.1 months compared to conventional paclitaxel	Clinical retrospective study	[87]
   Curcumin-paclitaxel core- shell nanoparticles	Drug-resistant ovarian cancer (SKOV3-TR30)	Synergistic anti-ovarian cancer effects; reversed drug resistance by inhibiting P-gp efflux and tumor cell migration	Preclinical	[88]
   RNA nanoparticles with HER2 aptamers (XBP1 siRNA)	HER2+ breast cancer mouse model	Strongly bound to tumors; XBP1 deletion impaired angiogenesis and promoted chemotherapy sensitization	Preclinical	[89]

   A comprehensive review of preclinical studies reveals a field rich with innovation, successfully demonstrating proof- of-concept across a wide range of models (Table 2). Liposomal and polymeric nanoparticles remain the most mature and widely studied platforms due to their biocompatibility and versatile chemistry. For example, the co-delivery of doxorubicin and curcumin (a natural P-gp inhibitor) in liposomes has been shown to significantly increase apoptosis in resistant MCF-7/ADR breast cancer

   cells compared to free doxorubicin [90]. Similarly, polymeric micelles co-loading paclitaxel and the P-gp inhibitor pluronic have demonstrated superior tumor growth inhibition in xenograft models of drug-resistant ovarian cancer [91]. These studies provide strong evidence that the co-encapsulation strategy effectively re-sensitizes resistant tumors to conventional chemotherapy. The strength of this body of work lies in the consistent validation of these concepts in vitro and in animal models; its primary weakness is that very

   few of these highly specific, multifunctional systems have advanced to clinical trials.

   Despite the wealth of promising preclinical data, the journey to clinical approval is fraught with challenges, including manufacturing scalability, batch-to-batch consistency, long-term toxicity concerns, and the immense cost of clinical trials. The most significant gap between preclinical success and clinical application is the "bench-to- bedside" transition. While many systems, such as the mesoporous silica nanoparticles designed for stimuli- responsive cisplatin release (Table 2), show remarkable efficacy in controlled laboratory settings, their behavior in the heterogeneous human patient population is difficult to predict [92]. Therefore, a critical future direction is the development of more predictive preclinical models, such as patient-derived xenografts (PDXs) and complex organ-on-a-chip systems, that better replicate human tumor biology and the systemic effects of nanomedicines. Furthermore, a concerted effort is needed to standardize regulatory pathways for these complex combination products, which will be essential to streamline their clinical development and ultimately realize their therapeutic potential for patients with drug-resistant cancer.

3. Challenges and Future Directions

   Despite the immense promise and rapid pace of innovation, the widespread clinical translation of multifunctional nanoparticles for MDR reversal faces significant biological, technical, and regulatory hurdles. These challenges must be systematically addressed to bridge the gap between compelling preclinical data and routine clinical use. The future of the field will depend on developing a deeper understanding of nanoparticle-host interactions, creating robust and scalable manufacturing processes, and designing smarter, more predictive therapeutic platforms.

   A primary biological barrier is the complex and often unpredictable interaction of nanoparticles with the host physiological system, leading to concerns regarding toxicity and immunogenicity. Upon entering the bloodstream, nanoparticles are immediately coated with a layer of host proteins, forming a "protein corona" that alters their original engineered identity [93]. This bio-corona can fundamentally change the nanoparticle's biodistribution, clearance rate, and cellular uptake, often directing them away from the tumor and toward organs of the reticuloendothelial system like the liver and spleen, thus limiting efficacy and potentially causing off-target toxicity. Mitigating these effects, perhaps through the design of advanced "stealth" coatings or by pre- saturating the corona with specific proteins, remains a critical area of investigation [94].

   From a technical standpoint, manufacturing and regulatory approval present formidable challenges. The complexity of multifunctional nanoparticles, often involving multiple components like polymers, lipids, drugs, and genetic material; makes large-scale, reproducible manufacturing under Good Manufacturing Practice (GMP) standards incredibly difficult. There is a pressing lack of standardized protocols and quality control metrics for characterizing these hybrid systems, which complicates regulatory evaluation. National and international regulatory bodies are still adapting to these novel therapeutic modalities, and establishing clear, predictable pathways for clinical approval is essential for encouraging investment and innovation in the field [95].

   Looking forward, the next generation of nanotherapeutics will likely be defined by enhanced biomimicry and greater integration of diagnostic and therapeutic functions. A key priority is the development and adoption of more sophisticated preclinical models that can better predict clinical outcomes. Organ-on-chip platforms that incorporate 3D cell cultures, physiological fluid flow, and multiple cell types are emerging as powerful tools for studying nanoparticle transport and efficacy in a human-relevant context, especially for MDR studies [96], [97], [98]. Furthermore, the convergence of diagnostics and therapy into single "theranostic" platforms represents a major advance. Future research will focus on creating modular nanoparticles that can not only deliver a therapeutic payload to inhibit efflux pumps but also carry agents to confirm delivery, monitor tumor response, and stratify patients who are most likely to benefit, thus paving the way for a new era of personalized nanomedicine against drug-resistant cancer.

4. Conclusion

ABC transporter-mediated multidrug resistance remains a linchpin in chemotherapy failure, driving tumor recurrence through efflux pump overexpression that compromises therapeutic efficacy. This sudy has synthesized compelling evidence that multifunctional nanoparticles represent a paradigm-shifting approach to circumvent this resistance through rational engineering and combinatorial mechanisms. Key advancements include nanocarriers that co-deliver chemotherapeutics with ABC inhibitors to ensure spatiotemporal co-localization, gene-silencing platforms that downregulate transporter expression, and stimuli-responsive systems that exploit tumor microenvironment cues for site- specific payload release. Emerging technologies such as DNA nanobots and neutrophil-guided "Trojanbots" further demonstrate unprecedented precision in overcoming biological barriers. Collectively, these innovations substantially enhance intracellular drug accumulation while minimizing systemic toxicity, effectively re-sensitizing resistant malignancies to conventional therapies.

Despite these promising developments, significant challenges impede clinical translation. The formation of protein coronas unpredictably alters nanoparticle biodistribution, diverting substantial doses to reticuloendothelial organs and compromising tumor targeting. Manufacturing complexities inherent to hybrid nanosystems particularly those integrating polymeric, inorganic, and biological components, hinder scalable Good Manufacturing Practice (GMP) production and batch consistency. Moreover, the stark discrepancy between preclinical success and clinical performance underscores the limitations of current animal models in replicating human tumor heterogeneity and transporter redundancy. Fewer multifunctional nanotherapeutics advance beyond Phase I trials, reflecting inadequate predictive validity of existing evaluation frameworks.

Future research must prioritize four critical avenues:

1. Advanced Biomimicry: Developing "stealth" nanoparticles with pre-saturated protein coronas to evade immune recognition and enhance tumor- specific accumulation.

2. Multi-Stimuli Systems: Engineering nanoplatforms responsive to dual tumor microenvironment triggers (e.g., pH/enzyme or redox/hypoxia) to ensure uniform drug release in heterogeneous lesions.

3. Integrated Theranostics: Combining efflux inhibitors with real-time monitoring agents (e.g., MRI/PET tracers) to monitor biodistribution and therapeutic response simultaneously.

4. Personalized Approaches: Creating modular nanoparticles adaptable to patient-specific transporter profiles using AI-driven design and validated through physiologically relevant models

Acknowledgment

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this chapter. We humbly acknowledge and thank all our previous teachers and mentors whose guidance and wisdom have illuminated our paths. We also acknowledge all the help and support received from all the stakeholders, friends and well-wishers to compile this review article successfully.

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